The CAR T-cell therapy (Chimeric Antigen Receptor) has been billed as a radical new way to cure cancer.

But since the US FDA approved the first cell-gene therapy to treat leukemia in 2018, the technology has not really caught on in the mainstream.

So is there a place for CAR-T therapy within the wider immuno-oncology market?

According to the latest data from Grandview Research, the market is about to explode from US$1 billion in 2020 to US$20.3 billion by 2028, with two million patients in 10 years.

Australia is also starting to adopt the technology. Earlier this month, the government approved the use of Yescarta, a type of CAR-T cell therapy thats used to treat patients with certain types of lymphoma a form of blood cancer.

Its expected up to 300 Australians per year will benefit from these therapies, which are available at selected public hospitals.

A handful of ASX-listed companies are also rapidly advancing their research into the T-cell therapy space.

Immutep (ASX:IMM) announced on Friday a patent grant in China for the use of its LAG-3 antibody molecules.

LAG-3 (or Lymphocyte Activation Gene-3) is a gene that codes a protein involved in the regulation of the immune system.

Immutep is currently studying how the LAG-3 immune control mechanism reacts with its lead drug,eftilagimod alpha.

Another ASX-listed company, AdAlta (ASX:1AD), has also just flagged its intention to enter the CAR-T space, signing a collaboration agreement with Carina Biotech last week.

AdAlta mainly focuses on its lead drug candidate, i-body AD-214, to treat fibrosis, and its entrance into CAR-T is a welcome boost for the sector.

Stockhead caught up with AdAlta CEO, Dr Tim Oldham, to ask him how CAR-T works and what the current challenges are.

CAR-T is all about reprogramming the bodys own immune system to fight cancer, Oldham explained to Stockhead.

T-cells themselves are a type of white blood cells found naturally, which patrol the body for signs of disease.

T-cells do this by using the receptors found on their surface to latch on to antigens of cancer cells, which are then killedby injecting them with toxins.

The trouble is, cancer cells are smart and can avoid detection.

The cancer cells are really good at hiding from the immune system by disguising themselves so the T-cells dont recognise them, Oldham said.

And so our immune system doesnt do a great job of tracking down cancer.

What the CAR-T cell therapy does is to reprogram the T-cells to break through the cancer cells defences.

The first step of the process is to collect white blood cells from the patients blood using a procedure called leukapheresis.

When the white blood cells are removed and T-cells separated, they are sent to the lab which then genetically modifies the patients T-cells receptors to recognise the specific cancer.

Its essentially like putting on a GPS on the T-cells back into your body, says Oldham.

According to Oldham, there are a few obstacles that need to be overcome before CAR-T therapies could really go mainstream.

Firstly, the therapy is currently only effective on blood cancers, and not on solid tumours.

Weve been really successful with blood cancers because its relatively easy to find tumour-specific antigens in blood cells, explained Oldham.

Solid tumours on the other hand, are much harder for three reasons.

Firstly, theres not as many tumour specific antigens known and the tumour cells dont necessarily express them all, so its much harder to zoom in and target these solid tumour cells.

The second problem is getting the T-cells into the solid tumour. With a blood cancer its easy because theyre all in the blood anyway.

The third challenge with targeting solid tumours, Oldham explained, is that a tumour is an environment thats designed to suppress the immune system to stop working. And this just makes it much harder for CAR-T cells to find and penetrate solid tumours.

Oldham says AdAltas collaboration with Carina will potentially address all three problems.

Our technology which we call i-bodies will enable us to really target the solid tumours, he said.

Oldham explained that AdAltas i-bodies are the next generation antibodies that are genetically modified and are approximately one-tenth the size of monoclonal antibodies.

The Carina technology meanwhile, will overcome the local penetration of the tumour in the immuno-suppression, and that combined with our i-bodies will give us a new way to hit CAR-T on solid tumours.

The other obstacle to mass adoption of CAR-T is the cost of these therapies.At the moment, prices are in the vicinity of US$400,000 for a single dose.

This is because every dose has to be made specific for each patient, Oldham said.

Another challenge is the safety, and there has been examples where patients have experienced really severe adverse events.

The safety issue is currently significant, but equally youre looking at a disease thats going to kill someone anyway.

Other ASX companies that focus on CAR-T therapies include Chimeric Therapeutics (ASX:CHM), Prescient Therapeutics (ASX:PTX), and Imugene (ASX:IMU).

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CAR-T therapy is potentially a $20bn market. Heres how it works and the ASX players in the space - Stockhead

NEW YORK, Aug. 30, 2021 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in allogeneic cellular medicines for inflammatory diseases, today reported operational highlights and financial results for the fourth quarter and full-year ended June 30, 2021 (FY2021).

During this calendar year we made significant progress in both regulatory and clinical outcomes for our lead product candidate, remestemcel-L, after experiencing a disappointing set-back last year said Silviu Itescu, Chief Executive of Mesoblast. We are pleased with recent recommendations by FDAs CBER to meet with the review team and address remaining CMC items for remestemcel-L in the treatment of steroid-refractory acute graft versus host disease in children. Additionally, our most recent meeting with the FDA has provided clarity on the pathway towards an emergency use authorization for remestemcel-L in the treatment of COVID ARDS.

Operational Highlights

Remestemcel-L Outcome of recent meeting with FDA on regulatory pathway for emergency use authorization in the treatment of COVID-19 ARDS:

Remestemcel-L in the treatment of steroid-refractory acute graft versus host disease (SR-aGVHD) in children:

Rexlemestrocel-L in the treatment of chronic heart failure and chronic low back pain:

Manufacturing

Financial Highlights

DETAILED CLINICAL ACTIVITIES FOR THE FISCAL YEAR FY2021

Remestemcel-L

Acute Respiratory Distress Syndrome due to COVID-19

Mesoblast recently presented results from the randomized controlled trial of remestemcel-L in 222 ventilator-dependent COVID-19 patients with moderate/severe acute respiratory distress syndrome (ARDS) at the biennial Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases conference hosted by the University of Vermont, Burlington, VT, and at the International Society for Cell & Gene Therapy (ISCT) Scientific Signatures Series event on Cell and Gene-Based Therapies in Lung Diseases and Critical Illnesses.

The presented data included improved respiratory function in patients treated with remestemcel-L, as well as 90-day survival outcomes showing remestemcel-L significantly reduced mortality by 48% at 90 days compared to controls in a pre-specified exploratory analysis of 123 treated patients under 65 years old. The trial had been halted after the third interim analysis since the 30-day primary endpoint would not be attained.

Key presentation findings were:

Mesoblast plans to move forward with an additional Phase 3 trial in COVID-19 ARDS with the next step being to agree with the FDA the final protocol and potency assay.

Inflammatory Bowel Disease Crohns Disease and Ulcerative Colitis

A randomized, controlled study of remestemcel-L delivered by an endoscope directly to areas of inflammation and tissue injury in up to 48 patients with medically refractory Crohns disease and ulcerative colitis commenced at Cleveland Clinic in October 2020. The investigator-initiated study is the first in humans using local cell delivery in the gut and will enable Mesoblast to compare clinical outcomes using this delivery method with results from an ongoing randomized, placebo-controlled trial in patients with biologic-refractory Crohns disease where remestemcel-L was administered intravenously.

Rexlemestrocel-L

Chronic Heart Failure

The results from the landmark DREAM-HF randomized controlled trial in 537 treated patients with chronic heart failure with reduced left ventricular ejection fraction (HFrEF) who received rexlemestrocel-L (REVASCOR) or control sham, demonstrated that a single dose of rexlemestrocel-L resulted in substantial and durable reductions in heart attacks, strokes, and cardiac deaths. The trials primary endpoint of reduction in volume overload related hospitalizations was not achieved. The results of this trial identify New York Heart Association (NYHA) class II HFrEF patients as the optimal target population for greatest rexlemestrocel-L treatment effect, and therefore a focus for developing rexlemestrocel-L in the largest market in heart failure.

The incidence of heart attacks and strokes were reduced by 60% over a median follow-up period of 30 months following a single dose of rexlemestrocel-L in the entire population of 537 treated patients. The incidence of death from cardiovascular causes was reduced by 60% in the 206 patients with NYHA class II disease, a significant reduction which was evident in both ischemic and non-ischemic subgroups as well as diabetic and nondiabetic patients.

The results also show that the NYHA class II patients in the control group, following an initial period of approximately 20 months of disease stability, progressed to cardiac death rates in-line with NYHA class III patients. NYHA class II patients treated with a single dose of rexlemestrocel-L did not show such cardiac death progression.

The combination of the three pre-specified outcomes of cardiac death, heart attack or stroke into a single composite outcome - called the three-point major adverse cardiovascular events (MACE) is a well-established endpoint used by the FDA to determine cardiovascular risk. Rexlemestrocel-L reduced this three-point MACE by 30% compared to controls across the entire population of 537 treated patients. In the NYHA class II subgroup of 206 patients, rexlemestrocel-L reduced the three-point MACE by 55% compared to controls.

Mesoblast expects feedback from the FDA in the next quarter on the potential pathway to US regulatory approval for rexlemestrocel-L in patients with chronic heart failure.

Chronic Low Back Pain due to Degenerative Disc Disease

The results from the randomized controlled trial of its allogeneic mesenchymal precursor cell (MPC) therapy rexlemestrocel-L in 404 enrolled patients with chronic low back pain (CLBP) due to degenerative disc disease (DDD) refractory to conventional treatments indicate that a single injection of rexlemestrocel-L+hyaluronic acid (HA) carrier may provide a safe, durable, and effective opioid-sparing therapy for patients with chronic inflammatory back pain due to degenerative disc disease, and that greatest benefits are seen when administered earlier in the disease process before irreversible fibrosis of the intervertebral disc has occurred. The trial's composite outcomes of pain reduction together with functional responses to treatment were not met by either MPC group.

The rexlemestrocel-L+HA treatment group achieved substantial and durable reductions in CLBP compared to control through 24 months across the entire evaluable study population (n=391) compared with saline controls. Greatest pain reduction was observed in the pre-specified population with CLBP of shorter duration than the study median of 68 months (n=194) and subjects using opioids at baseline (n=168) with the rexlemestrocel-L+HA group having substantially greater reduction at all time points (1, 3, 6, 12, 18 and 24 months) compared with saline controls. There was no appreciable difference in the safety of MPC groups compared to saline control over the 24-month period of follow-up in the entire study population. In subjects using opioids at baseline, the MPC+HA demonstrated a reduction in the average opioid dose over 24 months, while saline control subjects had essentially no change.

There is a significant need for a safe, efficacious, and durable opioid-sparing treatment in patients with chronic low back pain due to severely inflamed degenerative disc disease. Mesoblast has filed a request and expects to receive feedback from the FDA on the pathway to US regulatory approval in patients with chronic low back pain due to degenerative disc disease.

Intellectual Property

Mesoblast has an extensive patent portfolio with over 1,000 patents and patent applications across 77 patent families, and patent terms extending through 2041. These patents cover composition of matter, manufacturing, and therapeutic applications of mesenchymal lineage cells, and provide strong commercial protection for our products in all major markets, including the United States, Europe, Japan and China. During the fiscal year Mesoblast has significantly expanded its patent portfolio, focusing on areas of its strategic commercial interests.

Licensing agreements with JCR, Grnenthal, Tasly and Takeda highlight the strength of Mesoblast's extensive intellectual property portfolio covering mesenchymal lineage cells. Mesoblast will continue to use its patents to prosecute its commercial rights as they relate to its core strategic product portfolio. When consistent with the Companys strategic objectives, it may consider providing third parties with commercial access to its patent portfolio.

DETAILED FINANCIAL RESULTS

Financial Results for the Year Ended June 30, 2021 (FY2021)

In August we entered into a contractual amendment to extend the interest-only period of its current senior debt facility to at least January 2022 and as a result no loan repayments will be required prior to January 2022. Mesoblast is in active discussions to refinance the facility.

We expect to recognize the existing US$21.9 million of remestemcel-L pre-launch inventory on the balance sheet if we receive FDA approval.

As a result of the above and other remeasurements on revaluation of assets and liabilities, the loss after tax for FY2021 was US$98.8 million compared to US$77.9 million for FY2020. The net loss attributable to ordinary shareholders was 16.33 US cents per share for FY2021, compared with 14.74 US cents per share for FY2020.

Conference Call

There will be a webcast today, beginning at 7.00pm EDT (Monday, August 30, 2021); 9.00am AEST (Tuesday, August 31). It can be accessed via:https://webcast.boardroom.media/mesoblast-limited/20210826/NaN61036c41df5665001c97fc67

The archived webcast will be available on the Investor page of the Companys website: http://www.mesoblast.com

About Mesoblast

Mesoblast is a world leader in developing allogeneic (off-the-shelf) cellular medicines for the treatment of severe and life-threatening inflammatory conditions. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of late-stage product candidates which respond to severe inflammation by releasing anti-inflammatory factors that counter and modulate multiple effector arms of the immune system, resulting in significant reduction of the damaging inflammatory process.

Mesoblast has a strong and extensive global intellectual property portfolio with protection extending through to at least 2041 in all major markets. The Companys proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblast has completed Phase 3 trials of rexlemestrocel-L for advanced chronic heart failure and chronic low back pain. Remestemcel-L is being developed for inflammatory diseases in children and adults including steroid refractory acute graft versus host disease and moderate to severe acute respiratory distress syndrome. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

References / Footnotes

Forward-Looking Statements

This announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of Mesoblasts preclinical and clinical studies, and Mesoblasts research and development programs; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies, including multi-national clinical trials; Mesoblasts ability to advance its manufacturing capabilities; the timing or likelihood of regulatory filings and approvals, manufacturing activities and product marketing activities, if any; the commercialization of Mesoblasts product candidates, if approved; regulatory or public perceptions and market acceptance surrounding the use of stem-cell based therapies; the potential for Mesoblasts product candidates, if any are approved, to be withdrawn from the market due to patient adverse events or deaths; the potential benefits of strategic collaboration agreements and Mesoblasts ability to enter into and maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology; estimates of Mesoblasts expenses, future revenues, capital requirements and its needs for additional financing; Mesoblasts financial performance; developments relating to Mesoblasts competitors and industry; and the pricing and reimbursement of Mesoblasts product candidates, if approved. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

Release authorized by the Chief Executive.

For more information, please contact:

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Operational Highlights and Financial Results for the Year Ended June 30, 2021 - GlobeNewswire

Cryo-Cell International, Inc. (Symbol CCEL), The Leader In Cord Blood And Cord Tissue Cryopreservation Services, Today Announced That The Companys Common Stock Has Been Approved For Listing On The Nasdaq Capital Market (Nasdaq).

Trading to Begin August 31, 2021 with Current Ticker CCEL

MIAMI, Aug. 30, 2021 (GLOBE NEWSWIRE) -- Cryo-Cell International has met Nasdaqs stringent financial, liquidity and corporate governance listing requirements. As a result, Cryo-Cell will be listed on Nasdaq as of Tuesday, August 31st 2021. This is expected to improve the liquidity of Cryo-Cell common stock, broaden its institutional shareholder base and ultimately enhance long-term shareholder value.

Cryo-Cells Chairman of the Board and Co-Chief Executive Officer, David Portnoy, stated: I am pleased to announce Cryo-Cells uplisting to Nasdaq, a major financial milestone that the Company had been considering, as previously stated several months ago. I believe that the significant gap between Cryo-Cells current market valuation and our intrinsic value should narrow as our visibility in the investment community grows, and this is a step in that direction. Cryo-Cell International has transformed in 2021 from being a profitable cord blood bank to a fully integrated, biopharmaceutical company that is expected to provide much needed access to experimental treatments for patients at the upcoming Cryo-Cell Institute for Cellular Therapies.

About Cryo-Cell International, Inc.

Founded in 1989, Cryo-Cell International, Inc. is the worlds first private cord blood bank. More than 500,000 parents from 87 countries have entrusted Cryo-Cell International with their babys cord blood and cord tissue stem cells. In addition to its private bank, Cryo-Cell International has a public banking program in partnership with Duke University. Cryo-Cells public bank has provided cord blood for more than 600 transplantations and operates cord blood donation sites across the U.S in prominent hospitals such as CedarsSinai Hospital in Los Angeles and Baptist Hospital in Miami. Cryo-Cells facility is FDA registered, cGMP-/cGTP-compliant and licensed in all states requiring licensure. Besides being AABB accredited as a cord blood facility, Cryo-Cell was also the first U.S. (for private use only) cord blood bank to receive FACT accreditation for adhering to the most stringent cord blood quality standards set by any internationally recognized, independent accrediting organization. Cryo-Cell owns the exclusive rights to PrepaCyte-CB, the industrys most advanced cord blood processing technology.

Cryo-Cells mission has been to provide clients with state-of-the-art cord blood and cord tissue cryopreservation services, raise awareness of the opportunity for expectant parents to bank or donate their babys cord blood and support the advancement of regenerative medicine. In February 2021, Cryo-Cell entered into a license agreement with Duke University that transformed Cryo-Cell into an autonomous, vertically integrated cellular therapy company that will be able to treat patients.

For more information, please visitIR.cryo-cell.com

Forward-Looking Statement

Statements herein the terms believes, intends, projects, anticipates, expects, and similar expressions as used are intended to reflect forward-looking statements of the Company. The information contained herein is subject to various risks, uncertainties and other factors that could cause actual results to differ materially from the results anticipated in such forward-looking statements or paragraphs, many of which are outside the control of the Company. These uncertainties and other factors include the impact of the COVID-19 pandemic on our sales, operations and supply chain, the success of the Companys global expansion initiatives and product diversification, the Companys actual future ownership stake in future therapies emerging from its collaborative research partnerships, the success related to its IP portfolio, the Companys future competitive position in stem cell innovation, future success of its core business and the competitive impact of public cord blood banking on the Companys business, the success of the Companys initiative to expand its core business units to include biopharmaceutical manufacturing and operating clinics, the uncertainty of profitability from its biopharmaceutical manufacturing and operating clinics, the Companys ability to minimize future costs to the Company related to R&D initiatives and collaborations and the success of such initiatives and collaborations, the success and enforceability of the Companys umbilical cord blood and cord tissue license agreements, together with the associated intellectual property and their ability to provide the Company with royalty fees, and those risks and uncertainties contained in risk factors described in documents the Company files from time to time with the Securities and Exchange Commission, including the most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and any Current Reports on Form 8-K filed by the Company. The Company disclaims any obligations to subsequently revise any forward-looking statements to reflect events or circumstances after the date of such statements.

For more information, please contact:Corporate Communications / Investor RelationsDiane Glanz, Rph, PharmD. Telephone: +1 (813) 749-2195Email: Investors@Cryo-Cell.com

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Cryo-Cell International Announces Uplisting to The Nasdaq Capital Market - GlobeNewswire

Company Developing FDA Cleared Phase III Cellular Therapy for COVID-19 Aims to Work with Regulators for Ultra-Rapid Clinical Translation

ELK CITY, Idaho, Aug. 30, 2021 /PRNewswire/ -- Therapeutic Solutions International, Inc., (OTC Markets: TSOI), announced today filing of an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) to initiate a clinical trial of its StemVacs-V immunotherapy in patients with metastatic breast cancer.

On May 24th, 2021, the Company announced progress in its preclinical experiments supporting the use of the immunotherapy in human trials. Part of the experiments demonstrated superior activity of StemVacs-V to other immune system-based approaches that were cleared by the FDA to literally "choke" tumors to death by blocking their blood supply1.

"I am honored to be leading medical efforts in bringing this game-changing approach to patients with breast cancer," said Dr. James Veltmeyer, Chief Medical Officer of the Company. "The previous efforts to develop an immunotherapy to kill tumor blood vessels have yielded drugs such as Avastin, which despite limitations, possesses multi-billion dollars in annual sales. In my opinion the StemVacs-V approach is superior to others because it induces more potent and more diverse immune responses targeting cancer blood vessels."

"The filing of today's IND is a significant milestone demonstrating the ability of Therapeutic Solutions International to rapidly move a diverse immunotherapy product pipeline through the drug development cycle," said Famela Ramos, Vice President of Business Development. "We anticipate multiple synergies of our developmental efforts as our candidate's advance forward, with our lead candidate having been cleared by the FDA to initiate Phase III clinical trials.

"Through working with our advisors such as Dr. Francesco Marincola, Dr. Santosh Kesari, and Francisco Silva, who have all published on utilization of First-Generation tumor angiogenesis blocking immunotherapies2,3, we anticipate learning from previous experiences and to rapidly move forward in taking this approach to patients," said Timothy Dixon, President and CEO of the Company and co-inventor of the StemVacs platform. "We thank our collaborators who have worked tirelessly to make this IND filing a possibility in such a rapid manner."

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About Therapeutic Solutions International, Inc.Therapeutic Solutions International is focused on immune modulation for the treatment of several specific diseases. The Company's corporate website is http://www.therapeuticsolutionsint.com, and our public forum is https://board.therapeuticsolutionsint.com/

1 Therapeutic Solutions International Optimizes Targeting the "Achilles Heel" of Cancer Using Second Generation Tumor Endothelial Targeting Vaccine StemVacs-V iPSC (prnewswire.com)2 Safety of targeting tumor endothelial cell antigens | Journal of Translational Medicine | Full Text (biomedcentral.com)3 Cancer anti-angiogenesis vaccines: Is the tumor vasculature antigenically unique? | Journal of Translational Medicine | Full Text (biomedcentral.com)

ir@tsoimail.com

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Therapeutic Solutions International Files Investigational New Drug Application with FDA for Cancer Blood Vessel Targeting Immunotherapy StemVacs-V to...

Christopher R. Flowers, MD, discusses the current therapies used for patients with relapsed/refractory diffuse large B-cell lymphoma and goes into specifics of the L-MIND trial after the long-term follow-up.

Christopher R. Flowers, MD,department chair of the Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the current therapies used for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and goes into specifics of the L-MIND trial (NCT02399085) after the long-term follow-up.

There are multiple therapies and therapy combinations approved in this setting, including chimeric antigen receptor (CAR) T-cell therapy. The 2021 American Society of Clinical Oncology (ASCO) Annual Meeting provided some updated for trials in this space, including the multicenter, open-label, single-arm, phase 2 study L-MIND trial.

Transcription:

0:08 | What we have, however, seen is a dramatic change in the numbers of therapies that are available in the relapse setting. That's with the advent of polatuzumab [Polivy] combined with bendamustine and rituximab [Rituxan], tafasitamab [Monjuvi] combined with lenalidomide [Revlimid], and now loncastuximab tesirine [Zynlonta] approved in that third or later line space of therapy, and the advent of 3 different CAR T-cell therapies that are now approved in the relapse setting for DLBCL. Then selinexor [Xpovio] that's also approved in that space. So really a whole host of options. At this year's ASCO meeting, we saw an update on some of those trials, and particularly the one looking at the combination of tafasitamab and lenalidomide, or the L-MIND trial.

What were the design and efficacy of the L-MIND trial?

1:08 | When we look at the L-MIND trial, it's a trial that was published with updated results in Lancet Oncology in 2020 describing a patient population of about 81 patients. When you look at the characteristics of the population, the median age at the time of enrollment was about 72 years, which is relatively similar to what we would see for a general population of patients with DLBCL; 11% of those patients had a prior stem cell transplantation. This is generally an older patient population who did not have transplant as part of their course of care. The majority of patients had a median of 2 prior lines of therapy, so still relatively early in their treatment cycle. When you look at response rates, and particularly when you look at response rates by numbers or prior lines of therapy, what was presented in the updated results at ASCO showed for those patients who had 1 prior line of therapy, that the complete response rate was 48% versus those who had 2 or more prior lines of therapy, and the trial was divided about half and half between those 2 different groups. Those who had 2 or more prior lines of therapy had a complete response rate of 33%. The duration of response appeared to be quite durable for both groups being more than 44 months in both groups of responders.

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Reviewing Current Therapies in Relapsed DLBCL and the L-MIND Trial - Targeted Oncology

Shoreline Launches into Era of Cell Therapy with $4 Billion in Partnerships

Shoreline Biosciences, an immunotherapy company formed in 2020 during the early days of the COVID-19 pandemic, was propelled into the proverbial catbirds seat this summer with two mega-deals, and now plans to double its employee base from 50 to 100 in the coming six to nine months.

Shoreline Biosciences is developing an off-the-shelf, targeted, allogeneic approach to natural killer (NK) and macrophage cell therapies, which Kleanthis G. Xanthopoulos, Ph.D., chairman and CEO, believes is one-of-a-kind.

This summers deals with Kite Pharmaceuticals, a Gilead Company, and BeiGene totaling $4 billion and boasting combined upfront payments of over $120 million to further develop its induced pluripotent stem cell (iPSC) programs are potent validation of Shorelines technology as well as its management. They go a long way toward ushering in what Xanthopoulos called the era of cell therapy.

Shorelines growing success is based on two pillars: solid science and experienced management.

You have to have the high science, but also enormous institutional know how, Xanthopoulos told BioSpace. These cells are finicky. There are significant challenges in manipulating them. Our founders have 20 years experience in this field.

BeiGene and Kite share our vision, and have extensive experience themselves BeiGene is incredible in protein engineering and Kite pioneered CAR T therapies, he said. So, when they chose to partner with Shoreline, they had performed competitive analysis and were saying, in essence, we believe in you and your capabilities.

These partnerships allow Shoreline to fast-forward its platforms.

For a company to bring so much capital and synergy to work is incredibly powerful, unique, and differentiated, Xanthopoulos said. It is difficult to find another early-stage preclinical company that has this kind of recognition and validation.

The new clinical data from Fate Therapeutics regarding its NK and T cell therapies help the field, too.

The science is very comprehensive, and we believe it will bring those programs forward, renewing interest in pluripotent stem cells and NK cells, Xanthopoulos surmised.

Shoreline Biosciences is developing off-the-shelf allogeneic therapies, bringing the benefit of stem cell therapies to many more patients than is possible with autologous transplants.

For autologous therapies, Xanthopoulos explains, It is costly to take patient cells, manipulate them in the lab, add guided chimeric antigen receptors, and return them to the patients There also are issues with rejection, as well as the more significant issues of cytokine release syndrome. Patients with aggressive tumors dont have the four to six weeks that method requires.

Shorelines allogeneic approach, therefore, creates targeted, off-the-shelf stem cell therapies.

The only effective way to do this is to start with pluripotent stem cells that can differentiate into more than 200 cell types, Xanthopoulos said. At Shoreline, we differentiate into hemopoietic cells. We are focused on NK cells and macrophages.

We have, basically, released the brakes for proliferating and activating the NK cells, he said, by editing out a negative regulator of activation and proliferation to create what essentially is a supercharged cell that is more metabolically fitted.

Preclinical studies in animals show the cells resist exhaustion, conferring a better pharmacokinetic profile and the need for fewer cytokines. Importantly, those efforts have been validated by independent researchers, in many published papers.

Results indicate the combination of pluripotent stem cells and NK cells results in a greater ability to kill various tumor cells using 5- to 10-fold less IL2 and IL15. Consequently, Xanthopoulos said, The overall therapy is less expensive.

Shoreline Biosciences plans to take this program into early human trials in the second half of 2022.

In 2023, we expect to file one or two Investigational New Drug (IND) applications, he said.

The benefit of an allogeneic iPSC approach to therapeutics development is clear.

Source: BioSpace

You can perform a lot of genomic edits at the pluripotent state without a great many technical problems, he noted.

For example, transducing macrophages with chimeric antigen receptors (CAR) requires specialized vectors and results in low yields. But, if you start with pluripotent stem cells, you can make the modifications, isolate a single clone with the characteristics you want, and generate trillions of cells. With one patient dose requiring approximately 100 million cells, this method can lower the approximate $400,000 cost of therapy substantially.

To do this for NK cells, Shoreline Biosciences created a unique, powerful engine and then determined how to decorate the resulting cells. After considering such issues as cell signaling, targeting, and toxicity, Xanthopoulos said, We engineered what you can think of as hooks where antibodies recognize and interact tightly, for higher killing activity.

As Xanthopoulos, a serial entrepreneur who has founded and operated four previous biotech companies, told BioSpace, Ive never been more excited. Stem cell therapies are proven. They are the next frontier of medicine.

They arent in the distant future, either. I think the era of cell therapies is here and now, and will dominate the landscape going forward. If we learn to make less immunogenic therapies, stem cell therapeutics will continue to increase momentum.

As Shoreline looks to the future, it is building an expansive team and is continuing to hire in all categories. We plan to double to about 100 employees in the next six to nine months, and have several outstanding investors onboard.

Continued here:
Shoreline Launches with $4 Billion in Partnerships PharmaLive - PharmaLive

For Car-T therapy to become anything other than a niche hospital procedure it has to move into early treatment lines. Novartiss Kymriah seems unlikely to secure such an accolade, however, having today failed to beat autologous stem cell transplantation in a second-line lymphoma study.

For the Swiss group this is especially galling as Kymriahs two big competitors, Bristol Myers Squibbs Breyanzi and Gileads Yescarta, have just succeeded in similar trials. Still, it will be important to bear in mind trial design differences, though one take is that important fault lines are emerging between CD19-directed Car-T therapies.

On a cross-study basis this was already becoming apparent in these treatments approved salvage uses in second-line or later lymphoma, where for instance Yescarta and Breyanzi boast overall remission rates above 70% while Kymriahs is 50%, according to US prescribing information.

Second line

Now the battle lines move to second-line lymphoma, an important setting where patients have relapsed after or are refractory to front-line Rituxan plus chemo.

Belinda, the trial Novartis today said had failed, compared giving these patients Kymriah head to head against the standard of care of chemo followed, in responders, by autologous transplant. Novartis said Belindas primary endpoint, event-free survival (EFS), failed to show a benefit for Kymriah.

An important point is that Belinda allowed the option of platinum-based immunochemotherapy before dosing Kymriah or the standard of care, a fact that might have rendered any subsequent benefit statistically insignificant.

Bristols corresponding Transform and Gileads Zuma-7 studies had similar designs and also tested EFS as primary endpoint, though they did not have the immunochemotherapy option. On June 10 Bristol said Breyanzi had beaten chemo plus transplant in terms of EFS, as well as in terms of complete response rates.

Two weeks later Yescarta scored in Zuma-7, with Gilead quantifying the EFS benefit versus chemo and transplant as a 60% reduction in event risk (p<0.0001). There was also a benefit in overall remission rate; overall survival was insufficiently maturefor Transform and Zuma-7 alike.

Note: *all 2nd line after Rituxan + chemo, compared against standard of care/autologous transplant in responders; **included the option of platinum immunochemotherapy before Kymriah or SoC. BCL=B-cell lymphoma; DLBCL=diffuse large B-cell lymphoma. Source: company statements.

Next it will be time to pick apart the data, with a clear focus falling on the possible effect of Belinda's addition of platinum immunochemotherapy.

In terms of disease criteria, Zuma-7 enrolled only diffuse large B-cell lymphoma patients, while Transform and Belinda both specified aggressive B-cell lymphoma but allowed subjects with grade 3B follicular lymphoma, a less aggressive type.

The precise balance of baseline characteristics will be scrutinised to see whether the studies offer an apples-to-apples comparison. A similar thing goes for subsequent therapy. How many patients in each studys control cohorts went on to receive Car-T, and did this influence outcomes? How durable are responses and what will the gold standard of median overall survival tell us once it is reached?

Some answers should be forthcoming when full data from these recent interim analyses are presented, perhaps at Decembers Ash meeting. In the meantime doctors and analysts alike will digest the emerging data suggesting that Kymriah, the first Car-T therapy to make it to market, might not be the best.

Original post:
New fault lines emerge in Car-T therapy - Vantage

Patients with hematologic cancer are at risk for not producing antibodies following 2 doses of the COVID-19 vaccine and could be at a high risk for breakthrough infections, according to findings from a prospective cohort registry study (NCT04794387) published in Cancer Cell.1

Estimates from the Leukemia & Lymphoma Society (LLS) indicate that approximately 250,000 patients with hematologic malignancies within the United States will not have detectable antibodies following full vaccination with the COVID-19 vaccine. Additionally, findings from the analysis indicated that 75% of patients with hematologic malignancies produced antibodies against COVID-19 following full vaccination. Notably, patients with common B-cell malignancies had the lowest rate of seropositivity (range, 44%-79%). Overall, the seroconversion rate in patients with hematologic malignancies ranged from 46% to 85% following inoculation with both vaccines. Among a cohort of age- and sex-matched immunocompetent controls, the serological response was 100%.

Although some patients with hematologic malignancies will not mount a full antibody response compared to healthy individuals, vaccines are safe and offer protection to the majority of blood cancer patients, Gwen Nichols, chief medical officer at the LLS, said in a press release.2 But not everyone will be protected, and [patients with] blood cancer are at increased risk of serious illness and death from COVID-19. We encourage blood cancer patients to take every measure to protect themselves from COVID-19 by getting vaccinated and continuing to take preventative precautions. This includes wearing a mask, social distancing, and avoiding crowds and poorly ventilated indoor spaces.

Investigators pulled samples for the study from March 2021 to May 5, 2021. Fourteen-day antibody response was evaluated in 1495 patients who had received the second dose of the vaccine. The median patient age was 68 years (range, 16-110). In total, 652 patients received mRNA-1246 and 793 received BNT162b2 vaccines.

Additional findings from the study indicated that seronegativity was observed in nearly all patients with non-Hodgkin lymphoma, while 64 patients with Hodgkin lymphoma were seropositive. Seronegativity was also noted in 56% of patients with mantle cell lymphoma (MCL), 38% of those with marginal zone lymphoma, 26% of those with Waldenstrm macroglobulinemia, 22% of those with follicular lymphoma, and 21% of those with diffuse large B-cell lymphoma. Investigators reported that seronegativity was observed in those who had received no therapy within the past 2 years and those who had previously been treated with a number of B-cellsuppressive therapies, including anti-CD20 monoclonal antibodies, BTK inhibitors, and CD19 CAR T-cell therapy.

Moreover, of the 36% of patients with chronic lymphocytic leukemia (CLL) who did not generate spike antibodies, 66 of 235 patients reportedly did not receive therapy within the last 2 years. Investigators believe that disease may directly impair B-cell function. Additionally, high seronegative rates were noted among patients who were receiving treatment with BTK inhibitors, anti-CD20 monoclonal antibodies, or those who received a combination of the aforementioned therapies plus venetoclax (Venclexta).

Conversely, patients with acute myeloid leukemia, acute lymphocytic leukemia, and CLL had seronegativity rates of 9%, 12%, and 2.9%, respectively, as well as 5.3% of those with multiple myeloma. However, no patients with smoldering myeloma were reported as being seronegative.

Investigators assessed differences in response between both COVID-19 vaccines within a population of seronegative malignancies, including MCL, follicular lymphoma, and Waldenstrm macroglobulinemia (n = 845). The unadjusted logistic regression analysis found patients were more likely to mount an immune response to the mRNA-1273 vaccine vs the BNT162b2 vaccine (OR, 1.50; 95% CI, 1.06-2.06; P = .021; OR, 1.73; 95% CI, 1.12-2.42; P = .001). This was further supported by the regression model with adjustments for age, disease type, gender, vaccine, and cancer group utilizing 2 different models (OR, 1.48; CI, 1.06-2.06; P = 0.021; OR, 1.73; CI, 1.24-2.42; P = 0.001).

Many patients with hematologic malignancies are at risk of not producing antibodies after two doses of the mRNA SARS-CoV-2 vaccines. Differences in antibody responses between the two mRNA vaccine series are detected in patient populations that have a high seronegative rate. Providers should be aware that a substantial subset of vaccinated blood cancer patients may be at high risk of breakthrough COVID-19 infections. Further studies are needed to assess the status of the immune system in seronegative patients and develop options for protecting this vulnerable population, the investigators concluded.

Read more:
Risk of Breakthrough COVID-19 Infection May Be High in Population With Hematologic Malignancies - Cancer Network