Category Archives: Cell Medicine

Open-label basket trial will assess the safety and efficacy of Zepzelca in patients with advanced urothelial carcinoma, large cell neuroendocrine carcinoma of the lung, or homologous recombination deficient tumors

DUBLIN, March 24, 2022 /PRNewswire/ -- Jazz Pharmaceuticals, Inc. (Nasdaq: JAZZ) today announced the first patient was enrolled in EMERGE-201, a Phase 2 clinical trial evaluating the safety and efficacy of Zepzelca(lurbinectedin)as a monotherapy in three cohorts of patients with advanced urothelial carcinoma, large cell neuroendocrine carcinoma of the lung, or homologous recombination deficient (HRD) tumors who have progressed on a platinum-containing regimen. EMERGE-201 will primarily assess patient objective response rates (ORR), according to the Response Evaluation Criteria in Solid Tumors (RECIST).

"Even with the rapid advancements in medical technology and care delivery across many tumor types over the last decade, there still remain many patients who continue to face unmet needs and experience a high burden of morbidity and mortality," said Arielle Heeke, M.D., breast medical oncologist at the Levine Cancer Institute and a primary investigator in the EMERGE-201 trial. "With the EMERGE-201 trial now underway, we look forward to seeing the potential clinical impact of Zepzelca on advanced solid tumor cancers, including HRD cancers, that have limited approved treatment options other than traditional chemotherapy. The trial will evaluate if this treatment can elicit tumor response based upon the underlying biology of these cancers and Zepzelca's novel method of action."

"This trial initiation is an exciting milestone for Zepzelca's clinical development program, as we seek to evaluate its clinical utility beyond treating small cell lung cancer," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "Given Zepzelca triggers a cascade of events that can affect the activity of DNA binding proteins including transcription factors and DNA repair pathways we look forward to analyzing Zepzelca's activity in additional difficult-to-treat cancers where driver oncogenes are actively transcribed and DNA repair mechanisms are inefficient, such as urothelial carcinoma, large cell neuroendocrine carcinoma of the lung and HRD-positive tumors."

EMERGE-201 Trial Details

EMERGE-201 is a Phase 2, multicenter, open-label trial designed to assess the safety and efficacy of Zepzelca as a monotherapy in three cohorts of patients with solid tumors, who will receive3.2 mg/m2 doses of Zepzelca intravenously on day one of an every-three-week dosing cycle, until confirmed disease progression. The three cohorts are: patients with advanced urothelial carcinoma, large cell neuroendocrine carcinoma of the lung, or HRDtumors who have progressed on a platinum-containing regimen.

The primary objective is to determine Zepzelca's ability to improve patient outcomes, as measured by ORR. Key secondary endpoints include investigator-assessed progression free survival, time-to-response, duration of response, and disease control rate as assessed by RECIST, as well as overall survival in participants treated with Zepzelca. The trial is sponsored and is being conducted by Jazz Pharmaceuticals.

Approximately 20 sites in the U.S. will participate in this trial. Additional information about the trial, including eligibility criteria, can be found here.

About Zepzelca(lurbinectedin)

Zepzelcais an alkylating drug that binds guanine residues within DNA. This triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.

TheFDAapprovedZepzelcaunder accelerated approval inJune 2020for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The approval is based on overall response rate (ORR) and duration of response demonstrated in an open-label, monotherapy clinical study.In December 2021, Jazz and PharmaMar announced the initiation of LAGOON, a confirmatory Phase 3 clinical trial of Zepzelca for the treatment of patients with relapsed small cell lung cancer. If successful, LAGOON will serve as the confirmatory trial for Zepzelca to secure full approval in the U.S.

Zepzelca is a prescription medicine used to treat adults with small cell lung cancer that has spread to other parts of the body (metastatic) and who have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working. Zepzelca is approved based on response rate and how long the response lasted. Additional studies will further evaluate the benefit of Zepzelca for this use. Zepzelca is not approved as part of a combination therapy or as a first-line maintenance treatment for patients with extensive-stage small cell lung cancer.

Important Safety Information for Patients

Before receiving ZEPZELCA, tell your healthcare provider about all of your medical conditions, including if you:

Females who are able to become pregnant:

Males with female partnerswho are able to become pregnant should use effective birth control during treatment with and for 4 months after your final dose of ZEPZELCA.

Females who are breastfeeding or plan to breastfeed. It is not known if ZEPZELCA passes into your breastmilk. Do not breastfeed during treatment with ZEPZELCA and for 2 weeks after your final dose of ZEPZELCA. Talk to your healthcare provider about the best way to feed your baby during treatment with ZEPZELCA.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines may affect how ZEPZELCA works.

What should I avoid while using ZEPZELCA?

Avoid eating or drinking grapefruit, or products that contain grapefruit juice during treatment with ZEPZELCA.

ZEPZELCA can cause serious side effects, including:

Tell your healthcare provider right away if you develop:

Tell your healthcare provider right away if you develop symptoms of liver problems including:

The most common side effects of ZEPZELCA include:

These are not all of the possible side effects of ZEPZELCA.

Call your doctor for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Jazz Pharmaceuticals at 1-800-520-5568.

More information about Zepzelca, including Full Prescribing Information and Patient Information, is available here.

ZEPZELCA is a trademark of Pharma Mar, S.A. used by Jazz Pharmaceuticals under license.

About Urothelial Carcinoma

Urothelial carcinoma (UC) is the fourth most common tumor in the United States and is highly aggressive compared to other tumor types.[1] UC tumors often times spread locally, causing them to become more advanced and difficult to treat. Progressive disease after frontline chemotherapy is characterized by a short survival.[2]

About Large Cell Neuroendocrine Carcinoma

Large cell neuroendocrine carcinoma (LCNEC) is a rare type of cancer that can occur in the lungs and colon. There is no standard of care for LCNEC in lung cancer due to limited data on its pathology and clinical trials, making it a condition with great unmet needs in treatment and management.[3]

About Homologous Recombination Deficient-Positive Tumors

Homologous recombination deficiency (HRD) occurs across a variety of solid tumors including endometrial, biliary tract, urothelial, breast, pancreatic, gastric and esophageal. HRD hinders the body's essential mechanism that repairs damaged DNA in cells.[4] HRD tumors are seen in almost a fourth (17.4%) of tumors across 21 cancer types.

About Jazz Pharmaceuticals plc

Jazz Pharmaceuticals plc (NASDAQ: JAZZ) is a global biopharmaceutical company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing life-changing medicines for people with serious diseasesoften with limited or no therapeutic options. We have a diverse portfolio of marketed medicines and novel product candidates, from early- to late-stage development, in neuroscience and oncology. Within these therapeutic areas, we are identifying new options for patients by actively exploring small molecules and biologics, and through innovative delivery technologies and cannabinoid science.Jazz is headquartered in Dublin, Ireland and has employees around the globe, serving patients in nearly 75 countries. For more information, please visit http://www.jazzpharmaceuticals.com and follow @JazzPharma on Twitter.

Caution Concerning Forward-Looking Statements

This press release contains forward-looking statements, including, but not limited to, statements related to Jazz Pharmaceuticals' belief in the potential of Zepzelca to provide a potentially new therapeutic option for certain solid tumor types and other statements that are not historical facts. These forward-looking statements are based on Jazz Pharmaceuticals' current plans, objectives, estimates, expectations and intentions and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, effectively launching and commercializing new products; obtaining and maintaining adequate coverage and reimbursement for the company's products; delays or problems in the supply or manufacture of the company's products; and other risks and uncertainties affecting the company, including those described from time to time under the caption "Risk Factors" and elsewhere in Jazz Pharmaceuticals' Securities and Exchange Commission filings and reports (Commission File No. 001-33500), including Jazz Pharmaceuticals' Annual Report on Form 10-K for the year ended December 31, 2021 and future filings and reports by Jazz Pharmaceuticals. Other risks and uncertainties of which Jazz Pharmaceuticals is not currently aware may also affect Jazz Pharmaceuticals' forward-looking statements and may cause actual results and the timing of events to differ materially from those anticipated. The forward-looking statements herein are made only as of the date hereof or as of the dates indicated in the forward-looking statements, even if they are subsequently made available by Jazz Pharmaceuticals on its website or otherwise. Jazz Pharmaceuticals undertakes no obligation to update or supplement any forward-looking statements to reflect actual results, new information, future events, changes in its expectations or other circumstances that exist after the date as of which the forward-looking statements were made.

Media Contact:Kristin BhavnaniHead ofGlobal Corporate CommunicationsJazz Pharmaceuticals plcCorporateAffairsMediaInfo@jazzpharma.comIreland+353 1 637 2141U.S. +1 215 867 4948

Investors:Andrea N. Flynn, Ph.D.Vice President, Head, Investor RelationsJazz Pharmaceuticals plcinvestorinfo@jazzpharma.comIreland +353 1 634 3211U.S. +1 650 496 2717

References

1 Kim M, Jeong CW, Kwak C, et al. Are urothelial carcinomas of the upper urinary tract a distinct entity from urothelial carcinomas of the urinary bladder? Behavior of urothelial carcinoma after radical surgery with respect to anatomical location: a case control study. BMC Cancer 15, 149 (2015).2 Tanaka M, Sonpavde G. Diagnosis and management of urothelial carcinoma of the bladder. Postgrad Med. 2011 May;123(3):43-553 Lindsay CR, Shaw EC, Moore DA, et al. Large cell neuroendocrine lung carcinoma: Consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists. Br J Cancer. 2021;125:1210-1216. 4 Heeke AL, Pishvaian MJ, Lynce F, et al. Prevalence of homologous recombinationrelated gene mutations across multiple cancer types. JCO Precis Oncol. 2018;2018:PO.17.00286.

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SOURCE Jazz Pharmaceuticals plc

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Jazz Pharmaceuticals Announces First Patient Enrolled in EMERGE-201 Phase 2 Basket Trial Evaluating Zepzelca (lurbinectedin) Monotherapy in Patients...

Treatment for glioma has long relied on MRI imaging to track tumor markers and treatment response. But findings from a team at the University of Michigan Rogel Cancer Center, led by Carl Koschmann, M.D., pediatric neuro-oncologist at University of Michigan Health C.S. Mott Childrens Hospital and researcher with the Chad Carr Pediatric Brain Tumor Center, suggest a new method could provide additional data about tumor markers before changes appear on an MRI, indicating possible strategies to help clinicians address this aggressive form of cancer. The recent study appeared in Neuro-Oncology.

As part of a phase 1, multi-site clinical trial, Koschmanns team collected cerebrospinal fluid and plasma from patients with Diffuse Midline Glioma, or DMG, through blood draws and lumbar punctures over many months, collecting hundreds of samples. They wanted to track changes in cell-free tumor DNA as patients received treatment concurrent with the clinical trial.

We examined DNA floating in the plasma and CSF at various points in treatment and used a very sensitive machine called digital droplet polymerase chain reaction (ddPCR) to assess the fraction, called a variant allele fraction (VAF), of mutated DNA versus non-mutated, Koschmann said.

A higher VAF indicates more mutant DNA. Koschmanns team found that patients whose allele fraction went down after receiving the drug in the clinical trial took longer for the tumor to grow larger or relapse, data consistent with the teams expectations.

But the findings from the CSF also revealed a marker that hadnt been shown in this kind of study before, one that couldnt be found relying on MRI imaging alone.

When the treatment wasn't working and tumors were growing, as captured on an MRI, that didn't always correlate with the VAF rising and the tumor DNA getting worse, said Evan Cantor M.D., first author of the study who performed work at U-M and is now a pediatric neuro-oncology fellow at Washington University. More often, we saw a spike in the allele fraction in the tumor DNA before the tumor grew, on average about three to four months before.

Koschmann explains that this is the first study of its kind to collect serial CSF in a clinical trial for any type of glioma. It is very clear that DNA in the CSF can provide a lot of new information about the state of the tumor, he said.

The method falls under the genre of liquid biopsy, which Koschmann describes as an exciting new space in cancer care. For some types of cancer like leukemia, testing blood and bone marrow samples allows patients and physicians to follow the status of the disease and offers a thorough sense of treatment response. But for solid tumors, especially brain tumors, access to multiple metrics to measure tumor growth or response is not possible.

If you were to come into the clinic right now with a high-grade brain tumor, wed take an MRI and then make inferences from that imaging about how things are going. But theres a lot of handwaving about what it means, because its the only piece of data we have about how things are going, Koschmann said.

As these findings suggest, knowing that the increase in the allele fraction proceeds tumor growth, discovered through serial CSF sampling, could inform clinicians about different treatment needs much sooner than if only referencing MRIs. As a patient or patient family member, you don't want to wait until the MRI worsens to change course, Koschmann said.Having early information that you might need to adjust treatment is very valuable.

This study was conducted as an exploratory arm of a multisite phase 1 clinical trial across 15 institutions for pediatric patients with midline glioma tumors who have about a 12 to 18 month survival rate. Patients received a promising experimental therapy called ONC201 over the course of months and, in some cases, years.

Koschmann shared the findings from this study with the principal investigators planning the follow-up phase 2 clinical trial with ONC201 through the Pacific Neuro-Oncology Consortium (PNOC). Based on this, the investigators made serial spinal fluid collection standard for every patient on the clinical trial. Koschmann explains that this is one step closer to gathering enough data to see if this method can be integrated into future treatment options.

If this study validates our early findings, we should be ready to make this part of routine clinical care for patients with DMG even off trial. By rolling this out at trial sites across the country, were pressing the gas pedal on bringing this test to the clinic.

Paper cited: Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma, Neuro-Oncology.DOI: 10.1093/neuonc/noac030

Funding was provided by NIH/NINDS (K08-NS099427; R01-NS119231; R01NS124607; R01NS110572); Department of Defense (CA201129P1); the University of Michigan Chad Carr Pediatric Brain Tumor Center; the ChadTough Defeat DIPG Foundation; the DIPG Collaborative; Catching Up With Jack; The Pediatric Brain Tumor Foundation; Prayers from Maria; Yuvaan Tiwari Foundation; The Morgan Behen Golf Classic; and the Michael Miller Memorial Foundation. Clinical Trial was supported by Chimerix.

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Spinal fluid sampling used to track treatment response in pediatric glioma - Michigan Medicine

Dr. Zonghai Li, Founder, Chairman of the Board, Chief Executive Officer, and Chief Scientific Officer of CARsgen Therapeutics Holdings Limited, commented that, "This is the first Annual Results following CARsgen's listing on the Hong Kong Stock Exchange on June 18, 2021. In the past year, CARsgen has made important progress, especially in pipeline development, technology innovation, CMC capacity expansion, business development, and strengthening our leadership team. Driven by the vision of Making Cancer Curable, we will continue to advance our product pipeline, develop innovative technologies, and consolidate our global strategy. We believe that we can bring innovative and differentiated cell therapy to cancer patients around the world as soon as possible, creating value for investors and the public."

1. Rapid progress of pipeline products

CT053

CT053 is an autologous CAR T-cell product candidate against BCMA being developed for the treatment of relapsed/refractory multiple myeloma (R/R MM). It incorporates a CAR construct engineered by CARsgen that features a fully human BCMA-specific single-chain variable fragment with lower immunogenicity and increased stability, which reduces the self-activation of CAR T-cells in the absence of tumor associated targets.

CARsgen has completed subject enrollment in the pivotal Phase II trial in China (LUMMICAR STUDY 1). In addition, CARsgen has started the pivotal Phase 2 clinical trial in North America (LUMMICAR STUDY 2) and treated the first subject in the pivotal Phase 2 trial in August 2021. As communicated with the U.S. FDA, the company is adding outpatient administration of CT053 into its U.S. clinical investigations.

CARsgen plans to make regulatory submissions for marketing approval to the NMPA in the first half of 2022 and plans to submit the BLA to the U.S. FDA in 2023. The company also plans to conduct additional clinical trials to develop CT053 as an earlier line of treatment for multiple myeloma.

Additional data update from the Phase I/II study in China (LUMMICAR STUDY 1) and an integrated analysis in participants with R/R MM by high-risk factors have been available as posters at the 2021 American Society of Hematology ("ASH") Annual Meeting in December 2021.

CT041

CT041 is an autologous CAR T-cell product candidate against the protein Claudin18.2 (CLDN18.2) and has the potential to be first-in-class globally. CT041 targets the treatment of CLDN18.2 positive solid tumors with a primary focus on gastric/gastroesophageal junction cancer (GC/GEJ) and pancreatic cancer (PC). In addition to the investigator-initiated trials, CARsgen has initiated a Phase Ib clinical trial for advanced GC/GEJ and PC and a confirmatory Phase II clinical trial for advanced GC/GEJ in China, and initiated a Phase 1b clinical trial for advanced gastric or pancreatic adenocarcinoma in North America.

In North America, CARsgen has initiated the Phase 1b trial of CT041-ST-02 and has treated the first subject in July 2021.

In 2020 and 2021, CT041 received Orphan Drug designation from the U.S. FDA for the treatment of GC/GEJ and Orphan Medicinal Product designation from the EMA for the treatment of advanced gastric cancer. In November 2021, CT041 was granted PRIME eligibility by the EMA for the treatment of advanced gastric cancer. In January 2022, CT041 was granted Regenerative Medicine Advanced Therapy (RMAT) Designation for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma with CLDN18.2 positive tumors.

CARsgen plans to submit an NDA to the NMPA in China in the first half of 2024 and also plans to initiate a Phase 2 clinical trial in the second half of 2022 in North America and to submit the BLA to the U.S. FDA in 2024.

CT041 has demonstrated promising therapeutic efficacy and safety in the ongoing investigator-initiated trial. The updates on the investigator-initiated trial of CT041 have been presented at the European Society for Medical Oncology Congress 2021 ("ESMO Congress 2021").

CT011

CT011 is an autologous CAR T-cell product candidate with proof-of-concept clinical data for the treatment of hepatocellular carcinoma (HCC) and has the potential to be the first-in class globally. The company has completed enrollment of a Phase I trial in China.

CT032

CT032 is an autologous CAR T-cell product candidate against CD19 being developed for the treatment of B cell Non-Hodgkin's lymphoma (NHL). The company is conducting a Phase I/II clinical trial in China.

AB011

AB011 is a humanized monoclonal antibody product candidate against CLDN18.2 being developed for the treatment of CLDN18.2 positive solid tumors. During the second quarter 2021, CARsgen received supplemental application approval by CDE regarding the addition of a chemotherapy combination cohort with AB011 in Phase Ib, and the company has subsequently initiated the combination cohort of AB011 with chemotherapy. The company completed Phase I monotherapy cohort enrollment and initiated combination with chemotherapy.

The company plans to consult with the NMPA in the second half of 2022 and to initiate the subsequent Phase II clinical trial.

CT0180

CT0180 is an autologous T cell product engineered to express a fusion protein of GPC3-targeted antibody fused T cell receptor (aTCR). Preclinical studies have shown that CT0180 could effectively recognize and kill GPC3-positive hepatocellular carcinoma cells and significantly inhibit HCC tumor growth in mouse xenograft models with reduced cytokine release compared to GPC3-CAR T-cells in vitro and in vivo, which improve the safety and applicability of adoptive cell therapies.

CT0181

CT0181 is an autologous T cell product engineered with GPC3-targeted antibody fused T cell receptor co-expressing IL-7 cytokine. Preclinical studies have shown that CT0181 displays superior antitumor efficacy, T cell persistence, and immunological memory in solid tumors xenografts with low cytokine release compared to GPC3-CAR T-cells.

KJ-C2111 (CT0590)

CT0590 is an allogeneic CAR T-cell product candidate deploying THANK-uCAR technology that targets BCMA. CARsgen is developing CT0590 for the treatment of relapsed/refractory multiple myeloma (R/R MM). The company has initiated IIT trial to evaluate the efficacy and safety of CT0590 for the treatment of R/R MM.

In addition, there are other IND-enabling or pre-clinical stage product candidates: KJ-C1807 (CT048), KJ-C2112, KJ-C2113 and KJ-C2114.

2. Continuous Discovery and Technology Development

Despite the approved CAR T-cell products for the treatment of terminal line hematologic malignancies, there are still significant challenges. CARsgen strives to explore and develop innovative technology platforms to address these challenges to generate better cell therapy products to global cancer patients. The main focus includes:

These technologies are currently being developed in-house with global rights and can be used alone or combined to upgrade CARsgen's existing product candidates as well as to generate future innovative pipeline product candidates.

As of December 31, 2021, CARsgen had more than 300 patents of which more than 60 patents had been issued globally including China, the United States, Europe, and Japan.

3. Manufacturing Capacity Expansion

CARsgen has established in-house end-to-end clinical and commercial manufacturing capabilities for all three stages of CAR T manufacturing, including production of plasmids, lentiviral vectors, and CAR T-cells. With the clinical manufacturing facility in Xuhui, Shanghai and commercial GMP manufacturing facility in Jinshan, Shanghai, CARsgen has been manufacturing CAR T-cells in house to support clinical trials in China and manufacturing the lentiviral vectors in house to support clinical trials globally.

The company has been expanding manufacturing capacity in China and the U.S. to support both the clinical trials and the subsequent commercialization of pipeline products. The company has opened its CGMP manufacturing facility located at the Research Triangle Park (RTP) in Durham, North Carolina ("The RTP Manufacturing Facility"). The RTP Manufacturing Facility, with a total gross floor area of approximately 3,300 sq.m, will provide additional manufacturing capacity of autologous CAR T-cell products for 700 patients annually, and it will support the company's ongoing clinical studies and early commercial launch in North America and Europe.

4. External License Agreement

CAFA Therapeutics, a subsidiary of CARsgen Therapeutics, has entered into alicensing agreement with HK inno.N Corporation (KOSDAQ: 195940) to develop and commercialize CT032 and CT053, for the potential treatment of various cancers in the Republic of Korea, with an upfront and additional milestone payments totaling up to USD50 million plus up to double-digit percentage royalties on net sales. The collaboration with HK inno.N showcases CARsgen's commitment to establishing more external partnerships with leading pharmaceutical companies to maximize the application of its technology platform and the value of its product pipeline to benefit more cancer patients globally.

About CARsgen Therapeutics Holdings Limited

CARsgen is a biopharmaceutical company with operations in China and the U.S. and is focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors. The Company has built an integrated cell therapy platform with in-house capabilities that span target discovery, antibody development, clinical trials, and commercial-scale manufacturing. CARsgen has internally developed novel technologies and a product pipeline with global rights to address major challenges of CAR T-cell therapies, such as improving the safety profile, enhancing the efficacy in treating solid tumors, and reducing treatment costs. The Company's vision is to become a global biopharmaceutical leader that brings innovative and differentiated cell therapies to cancer patients worldwide and makes cancer curable.

Contact Us

For more information, please visit https://www.carsgen.com/

SOURCE CARsgen Therapeutics

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CARsgen 2021 Annual Results: Steady Advancement in Innovative CAR T Products and Technologies - PR Newswire

Urology Times is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, Melissa R. Kaufman, MD, PhD, FACS, discusses the innovative use of stem cellderived treatments in urologic conditions such as stress urinary incontinence. Kaufman is a Professor of urology, Patricia and Rodes Hart Endowed Chair of Urologic Surgery, and Chief of Reconstructive Urology and Pelvic Health at Vanderbilt University Medical Center, Nashville, Tennessee.

The newest frontier of therapy for stress incontinence is regenerative medicine and stem cellbased therapies. The basis of these are defined as embryonic stem cells or adult stem cells. Of course, there is continued scientific and ethical debate regarding the use of pluripotent embryonic stem cells. Our current cell-based therapies are somatic multipotent cells that are derived from adult tissues. These cells are terminally differentiated, and they serve in the body as progenitor cells for renewal of local tissues. These therapies have the potential to restore, in stress incontinence, the external striated sphincter, and potentially even smooth muscle within the bladder, neuromuscular transmission, as well as blood supply. There have been several different cell types that have been studied for this over the decadesboth animal and human studies include bone marrow cells, mesenchymal stem cells, adipose-derived cells, umbilical cord cells, [and] total nucleated cells, but the most well-studied population has been muscle-derived cells. This focuses on harvesting skeletal muscle, and it's delivered back to the external urethral sphincter after being expanded with the goal of regenerating this muscle and restoring function and, hopefully, continence.

The first successful clinical trial of autologous myoblast was used in the Austrian group in 2007. This was for female stress incontinence and was published in The Lancet.1 This was pioneering work well over a decade ago. Unfortunately, in 2008, that publication was retracted due to numerous concerns about the trial design and data interpretation.2 This setback undoubtedly resulted in a substantial delay in advancing this technology. However, at the 2021 AUA meeting, data were presented from a large randomized, double blind placebo-controlled trial of autologous muscle-derived cells, revealing really promising results for several subsets of stress incontinence patients, including those with persistent or recurrent incontinence following surgical interventions.

Stem cell technology is truly a transformational opportunity in urology, and the first regenerative option to complete really rigorous clinical evaluation. The autologous muscle-derived cell product are muscle progenitor cells [that] originate from tissue harvested from a muscle biopsy in the thigh and, upon injection, engraft into existing dysfunctional target tissue to improve muscle function. The product is in clinical trials for not just stress incontinence in females, but post-prostatectomy incontinence in men, fecal incontinence, underactive bladder, tongue dysphasia, and even cardiac applicationsbroad-ranging reach of a technology that is pioneered for a urologic indication. It's most studied, however, in stress incontinence. There have been over 500 women who have been treated with this product across several continents during all the iterations of the clinical trials. It augments urethral sphincter function and has the potential to be a really durable treatment. It produces some local tissue changes, but not systemic effects. Most of the subjects were in a broader stress incontinence treatment group. There was a sub population of women with a very troublesome condition of persistent or recurrent incontinence following prior surgical interventions. They demonstrated remarkable efficacy, with up to 30% having basically 0 to 1 stress leaks on their diaries in the trial. This was a very afflicted baseline with very phenomenal results. Because this was an unmet medical need and a very serious condition, this technology was granted expedited regenerative medicine advanced therapy designation by the FDA, which should really help facilitate future trials and bringing us to millions of patients who could benefit.

Stress incontinence has an enormous impact on a woman's quality of life. The gamut of this impact ranges beyond the direct symptoms, including an increased risk for depression and anxiety, reduced participation in physical activity and all the profound effects that can have, negative impacts on productivity at work, and the ability to maintain healthy sexual relationships. It leads to a substantial reduction in day-to-day functioning for women suffering from this disease. Recurrent or persistent incontinence for women who have undergone prior interventions is not short lived. It's not self-limiting, and [it] can progress in severity over time. This can cause additional stress. Women in this particular group have really limited options for treatment, that's not responded to what we consider gold-standard therapies for stress incontinence. Due to this wide range of an increasing number of patients and an aging population who suffer from stress incontinence, we really needed development of novel and effective therapeutic options with minimal patient morbidity, which was a paramount concern. We're embarking on the next frontier in urology with cellular therapies, and this is a gratifying opportunity to be practicing today, and have the ability to potentially provide durable, safe treatments that really reverse pathology and regenerate native tissue. The applications of this technology are very broad, and the next decade of innovations in this space will be astounding and transformative of our current treatment strategies for countless urology patients to improve both the quantity and quality of life.

References

1. Strasser H, Marksteiner R, Margreiter E, et al. Autologous myoblasts and fibroblasts versus collagen for treatment of stress urinary incontinence in women: a randomised controlled trial. Lancet. 2007;369(9580):2179-2186. doi:10.1016/S0140-6736(07)61014-9

2. Kleinert S, Horton R. Retraction--autologous myoblasts and fibroblasts versus collagen [corrected] for treatment of stress urinary incontinence in women: a [corrected] randomised controlled trial. Lancet. 2008;372(9641):789-790. doi:10.1016/S0140-6736(08)61320-3

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SUI treatment reaches "new frontier with regenerative medicine and stem cellbased therapies - Urology Times

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Blocking arginine metabolism leads to improved metabolic health, weight loss

An investigational cancer drug that starves tumors of their energy supply also shows evidence of improving whole body metabolism, according to a new study in mice from Washington University School of Medicine in St. Louis. Shown are sections of liver from mice on a high-fat, high-sugar diet. On the left, more white space indicates greater fat accumulation in an untreated mouse. On the right, in a mouse treated with the drug, the liver shows less fat accumulation.

An investigational cancer drug that starves tumors of their energy supply also shows evidence of improving whole body metabolism, leading to improved weight control, according to a new study in mice from researchers at Washington University School of Medicine in St. Louis.

The findings are published in the journal Cell Reports Medicine.

In a group of mice genetically prone to obesity and in a separate group of mice that became obese due to a high-fat, high-sugar diet, treatment with the drug ADI-PEG 20 increased insulin sensitivity, improved cholesterol levels, reduced fat buildup in the liver and lowered inflammation. For the mice genetically prone to obesity from birth, treatment with the drug protected them from their typical weight gain. And for the mice that became obese on a high-fat, high-sugar diet, treatment with the drug caused the mice to lose weight.

The drug is being investigated for potential use as a treatment for a number of cancers, including sarcoma, breast and pancreatic cancers. The drug breaks down the amino acid arginine in the blood, which deprives cancer cells of a key source of fuel. The researchers became interested in studying the drug after finding that genes responsible for breaking down arginine are dialed up tremendously when the body is in a fasting state. They wondered if the drug could mimic this effect of fasting.

Indeed, the researchers found that the drug triggers cells to undergo a process called autophagy, or self-eating, a cellular-level housecleaning process. Cells undergoing autophagy burn their own cellular waste products for fuel. During fasting, when no new fuel is coming from the outside, cells shift to autophagy, turning inward for their fuel supply.

Giving this drug seems to mimic some of the metabolic and therapeutic effects of fasting, said senior author Brian DeBosch, MD, PhD, an associate professor of pediatrics. I was surprised by how large the effect was. In the mice prone to weight gain, the group that received the drug ended up weighing about 25% less than the mice that didnt get the drug. And in the mice on the high-fat, high-sugar diet, we saw similar weight loss from the drug. Also, we dont think that the preponderance of the drugs metabolic benefits are from changes in body weight. In fact, for several outcome measures, the metabolic changes preceded significant changes in weight.

The drug has been tested in clinical trials investigating its safety and efficacy in treating several tumor types, including breast, prostate, pancreatic and liver cancers. In general, metabolic therapies tend to have fewer side effects and are safer than chemotherapy, radiation and even newer immunotherapies used to treat cancer.

DeBosch, a pediatric gastroenterologist who treats patients at St. Louis Childrens Hospital, said the research team would like to conduct a clinical trial of the drug to see if it triggers similar metabolic benefits and weight loss in people who are overweight or obese. One question that remains is whether the drug is safe to take long term. Its not a small molecule, like a statin, that can be taken for decades. The drug is a protein, so there is a possibility that patients could develop an immune response to it over time. However, DeBosch still sees a potential role for such a treatment over a matter of weeks to months.

Many patients with obesity who are considering bariatric surgery must first lose some weight to make the procedure safer, DeBosch said. It can be difficult for such patients to lose up to 10% of their body weight before the surgery. This type of therapy could potentially serve as a bridge to help patients lose weight before bariatric surgery, to reduce the risk of complications during and after the procedure.

This work was supported by the National Institutes of Health (NIH), grant numbers 1R01DK126622-01A1, 1R01HL147968-01A1, 1R21AT010520-01, UL1TR002345 and R56 DK115764; a Pilot Research Award from the American Association for the Study of Liver Disease; an AGA-Gilead Sciences Research Scholar Award in Liver Disease; the AGA-Allergan Foundation Pilot Research Award in Non-Alcoholic Fatty Liver Disease; the Washington University Digestive Disease Research Core Center, grant number P30DK52574; the Washington University Diabetes Research Center, grant number P30DK020579; the Nutrition & Obesity Research Center, grant number P30DK056341; the Association for Aging Research Junior Faculty Award; the Robert Wood Johnson Foundation; the Washington University Center for Autophagy Therapeutics Research; the Longer Life Foundation; and a Washington University School of Medicine Pediatric Gastroenterology Research Training Grant, number T32DK077653.

Part of this study was funded via a sponsored research agreement awarded by Polaris Pharmaceuticals. DeBosch holds two patents related to the work. Co-author Bomalaski is an employee of Polaris Pharmaceuticals Inc.

Zhang Y, Higgins CB, Van Tine B, Bomalaski JS, DeBosch BJ. Pegylated arginine deiminase (ADI-PEG 20) drives arginine turnover and systemic autophagy to dictate energy metabolism. Cell Reports Medicine. Jan. 18, 2022.

Washington University School of Medicines 1,700 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, and is among the top recipients of research funding from the National Institutes of Health (NIH). Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Drug mimics beneficial effects of fasting in mice Washington University School of Medicine in St. Louis - Washington University School of Medicine in...

HOUSTON, Jan. 19, 2022 (GLOBE NEWSWIRE) -- Marker Therapeutics, Inc. (NASDAQ:MRKR), a clinical-stage immuno-oncology company specializing in the development of next-generation T cell-based immunotherapies for the treatment of hematological malignancies and solid tumor indications, today announced that the United States Food and Drug Administration (FDA) Office of Orphan Products Development has granted Orphan Drug designation to MT-601, a multi-tumor-associated antigen (MultiTAA)-specific T cell product optimized for the treatment of patients with pancreatic cancer.

The FDAs orphan drug designation underscores MT-601s potential as a treatment for pancreatic cancer, a cancer typically diagnosed at an incurable advanced stage with a total overall 5-year survival rate of 10%, said Peter L. Hoang, President & CEO of Marker Therapeutics. Our novel therapy has shown encouraging results in an ongoing Phase 1 trial sponsored by Markers partners at the Baylor College of Medicine. In results reported at the 2020 American Society of Clinical Oncology (ASCO) Virtual Annual Meeting, our therapy has demonstrated the potential to safely produce durable responses in combination with chemotherapy as a first-line treatment option for patients with advanced or metastatic pancreatic adenocarcinoma. The results also revealed that epitope spreading was consistent in responders to Multi-TAA-specific T cells. Following MT-401 for the treatment of post-transplant acute myeloid leukemia (AML), MT-601 is Markers second novel MultiTAA-specific T cell product to receive orphan drug designation and the first in a solid tumor indication, underscoring the potential of Markers multi-antigen targeting T cell therapy approach in both solid tumors and blood cancers.

Marker developed MT-601, a new product targeting six tumor-associated antigens (PRAME, NY-ESO-1, Survivin, MAGE-A4, SSX2, WT1) highly expressed in pancreatic cancer. The Company intends to initiate a Phase 1 multicenter study of MT-601 administered in combination with front-line chemotherapy to patients with locally advanced unresectable or metastatic pancreatic cancer. Marker designed the study to include an initial antigen escalation period followed by a dose escalation period and will enroll 20 25 patients for the study.

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The Company plans to file an Investigational New Drug Application (IND) for MT-601 for the treatment of pancreatic cancer in 2022.

Orphan designation is granted by the FDA Office of Orphan Products Development to advance the evaluation and development of safe and effective therapies for the treatment of rare diseases or conditions affecting fewer than 200,000 people in the U.S. Under the Orphan Drug Act, the FDA may provide grant funding toward clinical trial costs, tax credits, FDA user-fee benefits, and seven years of market exclusivity in the United States following marketing approval by the FDA. The granting of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval. For more information about orphan designation, please visit the FDA website at http://www.fda.gov.

About Marker Therapeutics, Inc.Marker Therapeutics, Inc. is a clinical-stage immuno-oncology company specializing in the development of next-generation T cell-based immunotherapies for the treatment of hematological malignancies and solid tumor indications. Markers cell therapy technology is based on the selective expansion of non-engineered, tumor-specific T cells that recognize tumor associated antigens (i.e. tumor targets) and kill tumor cells expressing those targets. This population of T cells is designed to attack multiple tumor targets following infusion into patients and to activate the patients immune system to produce broad spectrum anti-tumor activity. Because Marker does not genetically engineer its T cell therapies, we believe that our product candidates will be easier and less expensive to manufacture, with reduced toxicities, compared to current engineered CAR-T and TCR-based approaches, and may provide patients with meaningful clinical benefit. As a result, Marker believes its portfolio of T cell therapies has a compelling product profile, as compared to current gene-modified CAR-T and TCR-based therapies.

To receive future press releases via email, please visit: https://www.markertherapeutics.com/email-alerts.

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Marker TherapeuticsNeda SafarzadehVice President/Head of Investor Relations, PR & Marketing(713) 400-6451investor.relations@markertherapeutics.com

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MediaAmy Bonannoabonanno@soleburytrout.com

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Marker Therapeutics Receives FDA Orphan Drug Designation for its Multi-Antigen Targeted T Cell Therapy for Pancreatic Cancer - Yahoo Finance

Researchers from the RCSI University of Medicine and Health Sciences, AMBER, the SFI Research Centre for Advanced Materials and BioEngineering Research along with leading global medical technology company Integra LifeSciences, have announced new breakthrough for nerve repair therapies based on bodys own processes in the journalMatrix Biology.

The pre-clinical study showed that use of extracellular matrix (ECM) supports improved nerve fibre regeneration across large nerve defects without the need for application of additional cells or growth factors. In these pre-clinical trials, the teams novel ECM-loaded medical device known as a nerve guidance conduit, was shown to support improved recovery responses at eight weeks following the repair of traumatic nerve lacerations with substantial loss of tissue.

The research team found that by fine-tuning the combination and ratio of ECM proteins and loading them into the nerve guidance conduit, it was possible to support increased pro-repair inflammation, increased blood vessel density, and increased density of regenerating nerves, all as compared to standard of care. By mimicking the bodys nerve repair processes, this new approach may eliminate the need for additional stem cells and drug therapies.

Peripheral nerve injury is a major clinical problem and is known to affect more than 5 million people worldwide every year, leaving those afflicted with loss of motor or sensory function to muscles or skin. Current therapies to repair nerve damage involve transplanting the patients healthy nerves to repair damage or implanting an artificial nerve guidance conduit. The teams novel patented approach to nerve repair has been shown to increase the density of regenerating long-nerve structures, known as axons, and to generate a strong increase in blood vessel density to better support the regenerating tissues.

Commenting on the results, lead authors Drs. Alan Hibbitts and Zuzana Ko from the Tissue Engineering Research Group based at Dept. of Anatomy and Regenerative Medicine at RCSI, and AMBER, said:

In our lab-based trials, we discovered that at eight weeks post implantation our nerve guidance conduit had successfully improved the prognosis for nerve regeneration and repair over the current clinical gold standard. Our conduit supported clear improvements in nerve repair and blood vessel formation and most importantly, we saw that we could scale this up to approach very large nerve defects in our pre-clinical studies.

Regarding the success of this study, Prof. Fergal OBrien, Principal Investigator on the project and Professor of Bioengineering and Regenerative Medicine, Head of Tissue Engineering Research Group at RCSI and Deputy Director of AMBER, said the partnership between RCSI, AMBER and Integra LifeSciences was critical to ensure clinical relevance and a pathway from lab to patient.

Working with Integra Chief Scientist, Dr. Simon Archibald, the research had a clear focus to create a device based on scientific excellence with improved outcomes that would translate well through regulatory assessment, into the clinical setting, and ultimately, patients. This provides a more direct route to market and therefore the potential for faster real-world impact in improving patient quality of life.

Dr Simon Archibald, Chief Scientist at Integra LifeSciences added: We have partnered with Prof. Fergal OBrien and his team at RCSI to innovate new solutions in regenerative medicine since 2005, and over that time, we have rapidly accelerated the development and translation of new biomaterials. We are enthusiastic for the future potential of this iterative innovation to address long-gap nerve repair, building on our current leading clinical materials for short-gap nerve repairs. Placing Integra at the coalface of research enables us to bring our expertise to the heart of the scientific process and identify clinically relevant solutions based on cutting-edge science, to improve patient outcomes and the most efficient pathway from the lab to clinical setting.

Detailing his teams plans, Professor OBrien said: Our new ECM-enhanced nerve guidance conduits are part of my teams ongoing research to address long peripheral nerve defects in partnership with Integra LifeSciences. The outputs from this project will address increasingly challenging nerve defect distances with the ambition to relieve the current clinical reliance on grafted nerves and move into the next phase of pre-clinical trials. Our partnership with Integra LifeSciences has been essential to this process, and we look forward to an ambitious programme of work that will advance continued enhanced treatments for nerve damage and injury.

Reference: Hibbitts AJ, Ko Z, Kneafsey S, et al. Multi-Factorial Nerve Guidance Conduit Engineering Improves Outcomes in Inflammation, Angiogenesis and Large Defect Nerve Repair. Matrix Biology. Published online January 13, 2022. doi:10.1016/j.matbio.2022.01.002

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Researchers Harness the Cell Matrix To Repair Nerves - Technology Networks

NOW IS THE TIME TO SUPPORT REGENERATIVE MEDICINE

TORONTO, Jan. 19, 2022 /CNW/ - As The Government of Ontario prepares its 2022 Spring Budget, OIRM is raising awareness of the massive losses expected if critically important sector funding is not continued.

At OIRM, we understand the unprecedented financial challenges facing Ontario, particularly in the healthcare sector, and this makes it even more vital that we take full advantage of the vast potential of Ontario's newly established Regenerative Medicine ecosystem to address Finance Minister Bethlenfalvy's key priorities:

Ontario's innovative stem cell scientists are already saving lives, including state-of-the-art treatments for COVID recovery, as Sharon Charlebois can attest. After being admitted into ICU with COVID-19 at The Ottawa Hospital, Sharon attributes her survival to the stem cell treatment she received. Read Sharon's fully story here.

Stem cell science originated in Toronto 50 years ago with the ground-breaking discovery by Doctors James Till and Ernest McCulloch; a remarkable contribution to our provincial, and national, legacy.

At a time when the unprecedented commercial value of stem cell technologies are just beginning to be realized, Ontario's stem cell innovators are now at a crossroads. Without ongoing funding, Ontario stands to lose it competitive advantage and the opportunity to benefit from the burgeoning Regenerative Medicine commercial sector.

Catalyzed by an initial $25M investment from the provincial government in 2015, OIRM has since generated $174.5M (6.9-fold ROI) in leveraged funding and invested in cutting-edge technologies that generated an additional $332M (13-fold ROI) in Series A investment. OIRM support was a key factor in the path leading to the creation of BlueRock Therapeutics, one of the greatest Canadian biotech success stories, which was acquired by Bayer in 2019 for $1B (40-fold ROI) and is now a leading engineered cell therapy company.

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"BlueRock invested in the Ontario ecosystem because of work that OIRM had supported from Dr. Michael Laflamme (UHN). It was really the strength of the science under OIRM's guidance, in my view, that led to our decision to launch and build BlueRock Therapeutics in the Toronto-area. OIRM's support was critical to getting a small biotech launched. I would like to see that funding envelope increased to give the Institute the ability to bring these programs to a later phase of value creationsomething that would have the added benefit of creating more confidence in potential investors."- Dr. Bob Deans, Chief Technical Officer, BlueRock Therapeutics 2017-2020

It is reasonable to expect more opportunities like BlueRock to develop if Ontario continues to nurture stem cell research and innovation. Ontario is staring at a $1B economic opportunity by funding Regenerative Medicine advancements. But in 2020, while the California Institute for Regenerative Medicine was refunded at $5.5B USD, here at home the funding for OIRM was removed as part of a cost-cutting exercise, and unfortunately before a glowing report from a blue-ribbon international review panel that recommended renewed funding for OIRM.

OIRM is imploring government to reconsider its position and continue funding stem cell advancements in Ontario. An investment of $25M over 5 years will yield massive returns for Ontario.

At no point in history have public health and economic recovery been simultaneously prioritized by the provincial government as urgently as right now. Medical treatments are evolving rapidly, and if made-in-Ontario stem cell research remains a priority for The Government of Ontario, there is good reason to feel hopeful about the future.

OIRM is a passionate champion for healthcare providers and their patients as we build a healthier future for Ontario, Canada, and the world.

SOURCE Ontario Institute for Regenerative Medicine

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Ontario Institute for Regenerative Medicine (OIRM) - Urgent Appeal to The Government of Ontario - Yahoo Canada Finance

Cytokines TNF and IL-6 can cause severely damaging inflammatory effects as a result of stem cells attacking host cells of blood cancer patients

By BRANDON NGUYEN science@theaggie.org

Researchers at the UC Davis Medical Center recently discovered a novel treatment against graft-versus-host disease (GVHD), a potentially lethal inflammatory condition that can arise following stem cell transplantation, which treats blood cancers and disorders. Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) to treat some blood cancers and disorders involves injecting a donors bone marrow stem cells, also known as graft, into blood cancer patients undergoing chemotherapy and radiation therapy.

Dr. William Murphy, a professor at the UC Davis School of Medicine under the Department of Dermatology and Internal Medicine and senior author of the study, further explained what GVHD is under the context of blood cancers.

If we take stem cells from another source, usually trying to match as much as we can from a related source such as a sibling, there seems to be an anti-tumor effect, Murphy said. This desired, beneficial effect from stem cell transplantation is called the graft-versus-tumor (GVT) effect. But the graft-versus-host disease means those immune cells can also attack not just the cancer, but the recipient or patient, which occurs pretty often.

The medical dilemma Murphy and his team of researchers faced involved maximizing GVT effects while minimizing GVHD during stem cell treatment to help the patient effectively fight off the tumor. Logan Vick, a graduate student under Murphys lab at the UC Davis Medical Center and a co-author of the study, talked about the major findings that help minimize GVHD in allo-HSCT patients.

In graft-versus-host disease, something that can be picked up as a symptom is this release of cytokines, which are inflammatory proteins, Vick said. TNF and IL-6, which are two inflammatory cytokines, are often used as tools of the immune system to combat either viruses or different pathogens, but prolonged inflammation can have consequences. So by blocking these two cytokines, what we call a dual cytokine blockade, can help ameliorate GVHD.

The cytokines, TNF and IL-6, that Vick focuses on can cause a cytokine storm, which can occur during GVHD when donor immune stem cells attack the hosts healthy cells instead of the tumor and induce inflammation caused by cytokines. GVHD and the dangerous cytokine storm effect has been a problem for stem cell transplantation treatments, but Murphys team of researchers have just found a potential cure to GVHD while still maintaining the efficacy of the treatment.

Lam T. Khuat, a postdoctoral researcher at Murphys lab and the first author of the study, summarized the beneficial results from dual cytokine blockage.

Many treatments for GVHD involve suppressing the bodys immunity, which can inhibit beneficial GVT effects, Khuat said via email. For this reason, it was important to determine if blocking these cytokines impacted the GVT response. Fortunately, anti-tumor effects remained after the transplant and with the combined intervention.

Clinical methods have often employed single cytokine blockades; however, with the novel finding that dual cytokine blockades can minimize the proinflammatory responses induced by GVHD, the treatment can also be applied in other health conditions that require stem cell transplantation or reducing inflammatory side effects.

Normally, when you have an overactive immune system, whether its autoimmune disorders or GVHD or even in viral infections, the treatments sometimes blanket immunosuppression with steroids, Murphy said. Well, that works because they turn off the immune system, but in the case of cancer and viral infections, you want a working immune system. The beauty of using this double block, which can be applied in other clinical settings, is it doesnt suppress the immune system while preventing the inflammation and the damage.

Written by: Brandon Nguyen science@theaggie.org

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UC Davis researchers find dual cytokine blockage as a novel treatment against graft-versus-host disease in blood stem cell transplantations - The...

Vaccine-like mRNA Injection Can Be Used to Make CAR T Cells in the Body

Experimental immunotherapy can temporarily reprogram patients immune cells to attack a specific target via only a single injection of messenger RNA (mRNA), similar to the mRNA-based COVID-19 vaccines, according to a new study from researchers in the Perelman School of Medicine at the University of Pennsylvania.

The researchers, whose work was published on January 6 in Science, demonstrated the new approach with an mRNA preparation that reprograms T cellsa powerful type of immune cellto attack heart fibroblast cells. Heart failure is often driven in part by these fibroblast cells, which respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, impairing heart functiona condition called fibrosis. In experiments in mice that model heart failure, the reduction in cardiac fibroblasts caused by the reprogrammed T cells led to a dramatic reversal of fibrosis.

Fibrosis underlies many serious disorders, including heart failure, liver disease, and kidney failure, and this technology could turn out to be a scalable and affordable way to address an enormous medical burden, said senior author Jonathan A. Epstein, chief scientific officer at Penn Medicine and executive vice dean and the William Wikoff Smith Professor of Cardiovascular Research in the Perelman School of Medicine. But the most notable advancement is the ability to engineer T cells for a specific clinical application without having to take them out of the patients body.

The new technique is based on chimeric antigen receptor (CAR) T cell technology, which, until now, has required the harvesting of a patients T cells and their genetic reprogramming in the lab to recognize markers on specific cell types in the body. These specially targeted T cells can then be multiplied using cell culture techniques and re-infused into the patient to attack a specific cell type. The first CAR T cell therapy was developed by researchers from Penn and Childrens Hospital of Philadelphia and approved by the U.S. Food and Drug Administration in 2017 for use against certain leukemias and later approved for lymphoma that arise from immune cells called B cells.

Although CAR T cell technology is currently used primarily for treating cancers, with dramatic results in many otherwise hopeless cases, its developers have long envisioned harnessing the approach for other diseases. Indeed, Dr. Epstein and colleagues showed in a 2019 study that the standard CAR T cell approach can be used to attack overactive cardiac fibroblasts and restore heart function in a mouse model of heart failure.

However, this standard CAR T cell strategy would be problematic when directed against heart failure or other fibrotic diseases in humans. Fibroblasts have a normal and important function in the body, especially in wound healing. CAR T cells that are reprogrammed genetically to attack fibroblasts could survive in the body for months or even years, suppressing the fibroblast population and impairing wound healing for all that time.

Therefore, in the new study, Dr. Epstein and colleagues devised a technique for a more temporary and controllable, and procedurally much simpler, type of CAR T cell therapy. They designed mRNA that encodes a T-cell receptor targeting activated fibroblasts and encapsulated the mRNA within tiny, bubble-like lipid nanoparticles (LNPs) that are themselves covered in molecules that home in on T cells. That technology is also crucial to the mRNA COVID-19 vaccines now in use across the globe.

Standard CAR T cell technology involves modifying patients T cells outside the body, which is expensive and difficult to scale for common diseases or for use in less wealthy countries, said study co-author Drew Weissman, the Roberts Family Professor in Vaccine Research at Penn. Making functional CAR T cells inside the body greatly extends the promise of the mRNA/LNP platform.

Injected into mice, the encapsulated mRNA molecules are taken up by T cells and act as templates for the production of the fibroblast-targeting receptor, effectively reprogramming the T cells to attack activated fibroblasts. This reprogramming is very temporary, however. The mRNAs are not integrated into T-cell DNA and survive within T cells for only a few daysafter which the T cells revert to normal and no longer target fibroblasts.

The scientists found that, despite this brief duration of activity, injections of the mRNA in mice that model heart failure successfully reprogrammed a large population of mouse T cells, causing a major reduction of heart fibrosis in the animals and a restoration of mostly normal heart size and function with no evidence of continued anti-fibroblast T cell activity one week after treatment.

The researchers are continuing to test this mRNA-based, transient CAR T cell technology, with the hope of eventually starting clinical trials.

Along with Drs. Epstein and Weissman, the other co-corresponding authors are Haig Aghajanian, co-founder and vice president of research at Capstan Therapeutics; and Hamideh Parhiz, a research assistant professor of medicine at Penn. Joel Rurik, the lead author, is a PhD candidate in Dr. Epsteins laboratory.

Funding for the study was provided by the National Institutes of Health.

Adapted from a Penn Medicine News article, January 6, 2022.

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