Category Archives: Cell Therapy

The year 2021 played host to several developments in the treatment of chronic lymphocytic leukemia (CLL), including promising data related to novel Burton Tyrosine kinase (BTK) inhibitors such as zanubrutinib (Brukinsa) and the examination of the benefit of continuous vs time limited regimens, according to Matthew S. Davids, MD, MMSc.

Looking forward into the new year, Davids spotlighted some potential events that the clinicians in the space witness in the new year.

There are a lot of exciting things going on right now in CLL, he explained. I do expect [that] we are likely to see a label for ibrutinib [Imbruvica] plus venetoclax [Venclexta] in the frontline setting in 2022. This is the first time well have the option to have an all-oral novel agent time-limited regimen for frontline CLL. We also have emerging data for noncovalent BTK inhibitors, for example, pirtobrutinib [LOXO-305]; we saw some great data at the [2021 American Society of Hematology Annual Meeting & Exposition (ASH)] suggesting this drug can work even for patients who have progressed on first-generation covalent BTK inhibitors, even if theyve already had venetoclax. Its hard to always knows what the timeframe is for these types of approvals, but I do think well see at least evolving datasets for pirtobrutinib in 2022.

In an interview with CancerNetwork, Davids, a physician and director of clinical research in the Division of Lymphoma at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, highlighted potential FDA decisions that may take place in 2022, such as the potential approval of frontline ibrutinib/venetoclax and the decision to either approve or extend the label for ublituximab (TG-1101) and umbralisib (Ukoniq) in the treatment of CLL and small lymphocytic leukemia (SLL).

Please be sure to read part 1 of our 3-part End-of-Year Wrap Up series in which Yael Cohen, MD, discusses updates in the multiple myeloma space that took place in 2021.

Davids: There were several impactful abstracts at this years ASH meeting in CLL. For me, one of the more exciting ones that I saw was the [phase 3] CLL13 trial [NCT02950051].1 This is an almost 1000-patient study going on in Europe that is largely comparing various venetoclax-based combinations with chemoimmunotherapy. At this ASH meeting, we saw for the first time the minimal residual disease (MRD) data from the study. Some of the takeaways for me were that the venetoclax plus obinutuzumab [Gazyva] combination performed well [with] high rates of undetectable MRD. [It was] certainly much higher than with chemoimmunotherapy, which wasnt a huge surprise, but also much higher than venetoclax with rituximab [Rituxan], which is a little bit surprising that the CD20 antibody made such a big difference. The study also had a triplet regimen of ibrutinib, venetoclax, and obinutuzumab. Although it looked a little bit more potent than venetoclax/obinutuzumab on its own, I do think that the doublet performed quite well. [Thus], its an open question whether the third drug is actually needed in the up-front setting.

We also saw [cohort 1] data from phase 3 SEQUOIA study [NCT03336333] for the first time.2 This is a registrational study looking at zanubrutinib, a newer, more specific BTK inhibitor compared with bendamustine and rituximab. This was a positive study favoring the PFS with zanubrutinib and is likely to lead to a label for [the regimen], hopefully in the future, in CLL. Several other impactful studies were presented, [including] various combinations of Ibrutinib plus venetoclax, both in older patients, for example, in an update to the phase 3 GLOW study [NCT03462719],3 as well as in younger fit patients in an update to the phase 2 CAPTIVATE study [NCT02910583] which really showed very nice durable responses.4 We presented some of our data on the combination of ibrutinib plus fludarabine, cyclophosphamide, and rituximab for young patients with CLL. This also has proven to be quite durable in terms of deep responses, [including] a 97% PFS rate with about 40 months of follow up. [It is] not something that would be broadly applied to a large population of patients with CLL, but [it could be] for those very young, fit patients who might want the potential for a functional cure of their disease. We think that this is the type of regimen that should be explored in larger comparative studies.

There are 3 main areas that I would focus on here from 2021. One of them is the idea of longer-term follow-up with venetoclax plus obinutuzumab. We saw the publication of the [phase 3 CLL14 trial (NCT02242942)] earlier this year with 4-year follow-up [that showed] a 74% rate of progression-free survival (PFS) at 4-years in patients treated with 1 year of venetoclax plus obinutuzumab.5 To me, that was impactful [and] gave me the confidence that my patients can enjoy a long remission after 1 year of time limited therapy largely across the board with the possible exception of high-risk patients with TP53 aberrant disease. Those patients did have a shorter PFS, although it was still close to 4 years which is quite impressive.

We also saw longer-term data presented at the 2021 American Society of Clinical Oncology Annual Meeting on the phase 3 Elevate-TN study [NCT02475681].6 This is the registrational trial for the more specific BTK inhibitor acalabrutinib [Calquence] in the frontline setting; this also looks quite good. About 87% of the patients are progression free [at 48 months] when treated with acalabrutinib/obinutuzumab and a little bit lower with acalabrutinib alone but still very good results. Again, [this] gives a lot of confidence that we can use acalabrutinib as a continuous treatment.

The third area that was very impactful for clinical practice was the readout of the phase 3 Elevate-RR study [NCT02477696].7 This was a trial weve been waiting on for several years. Its a head-to-head study of the original BTK inhibitor ibrutinib compared with acalabrutinib in relapsed/refractory higher-risk patients with CLL. The study showed complete equivalence in terms of the efficacy; the median PFS was 38.4 months in both arms. But there were significant advantages from a safety perspective with acalabrutiniblower rates of cardiovascular disorders overall, less atrial fibrillation, less hypertension, less bleeding overall, and lower rates of other factors such as interstitial lung disease. For me, this was influential that for patients who are newly starting on a BTK inhibitor, Im now leaning more toward acalabrutinib even though we do have a long-standing experience with ibrutinib. Its still a great drug, but acalabrutinib is also now an appealing option for many patients with CLL.

With ublituximab and umbralisib [U2], we have some early-phase data with both of these drugs on their own and in combination that looked promising. That inspired the development of the phase 3 UNITY-CLL trial [NCT02612311]. Thats now the largest dataset that we have looking at the U2 regimen. The study randomized both frontline and relapsed/refractory patients in a stratified manner to U2 vs chlorambucil with obinutuzumab. Weve seen the data presented from that study suggesting a significantly longer PFS both in frontline and relapsed patients for U2 as compared with chlorambucil plus obinutuzumab. Also, the tolerability of umbralisib does look somewhat more favorable than what we expect from other PI3K inhibitor drugs that are already approved like idelalisib [Zydelig] and duvelisib [Copiktra], particularly in the frontline setting where it has not been possible to safely use those other drugs. They did show feasibility in the UNITY-CLL study in the frontline setting using U2. Thats the main dataset that the FDA will be reviewing as they decide on whether to extend the label of umbralisib to CLL and whether to approve, for the first time, ublituximab in this disease.

The ASH meeting in 2021 was a huge [event] for CAR T-cell therapy in diffuse large B-cell lymphoma. But for CLL, things were a little bit more quiet. We had seen data presented earlier in the year at the summer congresses on lisocabtagene maraleucel [Liso-cel; Breyanzi], a CD19-directed CAR T-cell [therapy for] relapsed CLL, [in the phase 1 TRANSCEND-CLL-004 study (NCT03331198)].8 Those data were published this year in 2021, which is very helpful to see and do look promising. The single-agent data for liso-cel show about a 45% complete response rate, and upwards of 80% or more patients achieving undetectable MRD. There were also some data presented earlier this year [regarding] a combination CAR T-cell therapy with ibrutinib. This is also with liso-cel, which is a promising combination. The numbers of patients treated are still pretty small; were awaiting larger datasets. I dont think its going to be too soon that were going to see an approval yet for a CAR T-cell therapy in CLL. [However], I do think this is a promising therapeutic modality for our patients, [and] it will eventually have a role in this disease. Im hopeful that well start to see larger datasets emerge soon.

There are a lot of exciting things going on right now in CLL. I do expect in 2022, we are likely to see a label for ibrutinib plus venetoclax in the frontline setting. This is the first time well have the option to have an all-oral novel agent, time-limited regimen for frontline CLL. I think thats exciting. We also have data emerging for noncovalent BTK inhibitors, for example, pirtobrutinib. We saw some great data at ASH suggesting this drug can work even for patients who have progressed on the first generation of covalent BTK inhibitors, even if theyve already had Venetoclax. Its hard to always knows what the timeframe is for these types of approvals but I do think well see at least evolving datasets for pirtobrutinib in 2022.

We also have the U2 regimen in development that the FDA will be reviewing in 2022, [in which theyll] decide on whether that will get a label. We have a number of important ongoing studies around the world looking to answer some of the key questions in the field. [There are] couple of them that Im most excited about, one [being] the phase 3 CLL17 study [NCT04608318], which has already launched in Europe led by the German CLL study group, helping to answer this key question of continuous vs time-limited frontline therapy. Which is better? That study [features] ibrutinib continuously vs 1 of 2 time-limited combinations: ibrutinib plus venetoclax or obinutuzumab plus venetoclax. We also are launching the phase 3 MAGIC study [NCT03836261] in 2022 here in the US and around the world. This is looking at whats the optimal combination partner for Venetoclax in the frontline setting; is it the BTK inhibitor acalabrutinib, or is it obinutuzumab? Its a phase 3 randomized trial comparing those 2 regimens, both given in an MRD-driven fashion. Were hoping that eventually will answer an important question about time-limited therapy in the field.

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End-of-Year Wrap Up: Examining Past, Present, and Future Developments in CLL - Cancer Network

The combination of tumor-infiltrating lymphocyte (TIL) cell therapy with lifileucel (LN-144) or LN-145 and pembrolizumab (Keytruda) demonstrated encouraging efficacy and safety in patients with advanced melanoma, head and neck squamous cell carcinoma (HNSCC), and cervical cancer who were nave to immune checkpoint inhibitors (ICIs), according to data from the phase 2 IOV-COM-202 (NCT03645928) and C-145-04 (NCT03108495) trials.1

The findings, which were presented during the 2021 SITC Annual Meeting, showed that in 14 patients with cervical cancer who comprised cohort 3 of the C-145-04 trial, the overall response rate (ORR) with LN-145 plus pembrolizumab was 57.1% (n = 8; 95% CI, 28.9%-82.3%); this included 1 complete response (CR), 6 partial responses (PRs), 1 unconfirmed PR, and 5 best responses of stable disease (SD). At a median follow-up of 7.6 months, 71.4% (n = 5/7) of patients experienced ongoing confirmed responses.

In cohort 1A of the IOV-COM-202 trial, 10 patients with melanoma who received lifileucel plus pembrolizumab achieved an ORR of 60.0% (n = 6; 95% CI, 26.2%-87.8%); this comprised 3 CRs, 3 PRs, and 3 best responses of SD. Moreover, 66.7% (n = 4/6) had ongoing confirmed responses at a median follow-up of 11.5 months.

In cohort 2A of the IOV-COM-202 trial, 18 patients with HNSCC who received LN-145 plus pembrolizumab achieved an ORR of 38.9% (n = 7; 95% CI, 17.3%-64.3%); this included 1 CR, 1 unconfirmed CR, 4 PRs, 1 unconfirmed PR, and 7 best responses of SD. Additionally, 50% (n = 3/6) of patients had ongoing confirmed responses at a median follow-up of 7.8 months.

The encouraging results for Iovance TIL plus pembrolizumab across several tumor types validate the combination of checkpoint inhibition and TIL cell therapy as a potential platform approach in solid tumors, Friedrich Graf Finckenstein, MD, chief medical officer of Iovance, stated in a press release.2 We observed response rates that are approximately double compared with what was seen with single-agent pembrolizumab in early-line melanoma and head and neck cancers, as well as second-line cervical cancer. We are eager to continue our investigation of TIL combinations in melanoma, head and neck, cervical and nonsmall cell lung cancer patients in need of treatment options that provide higher response rates, and deeper responses with more complete responses.

ICIs are a key component of standard-of-care treatment for several advanced cancers. TIL therapies such as lifileucel have produced encouraging efficacy in patients with advanced cancer following failed treatment with ICIs. Early-line treatment with pembrolizumab monotherapy has produced ORRs ranging from 33% to 17% in patients with advanced melanoma and HNSCC, respectively.3,4 However, novel early-line combination regimens are required to further improve response rate and depth.

Regarding IOV-COM-202, cohort 1A included patients with unresectable metastatic melanoma who were nave to antiPD-1/PD-L1 agents (n = 12) and cohort 2A comprised of patients with advanced, recurrent, or metastatic HNSCC who were also nave to antiPD-1/PD-L1 (n = 19). Regarding C-145-04, cohort 3 was comprised of patients who had stage IVB, persistent, recurrent, or metastatic cervical cancer and who did not receive prior therapy except for chemoradiation or surgery for locoregional disease (n = 24).

The key eligibility criteria for the 2 trials required that patients have at least 1 resectable lesion for TIL manufacturing, with a diameter of at least 1.5 cm following resection. Patients also needed to have at least 1 measurable lesion for investigator response assessment per RECIST v1.1 criteria, and an ECOG performance status of either 0 or 1.

Patients were enrolled from March 2019 through August 2021. Participants underwent tumor resection for TIL manufacturing before receiving 1 dose of pembrolizumab at either 200 mg or 400 mg. Notably, patients in the C-145-04 trial were required to take a 200-mg dose of the immunotherapy compared with IOV-COM-202, which allowed patients to receive either dose.

The first dose of pembrolizumab was administered prior to nonmyeloablative lymphodepletion (NMA-LD), which was comprised of 2 daily doses of cyclophosphamide at 60 mg/kg on days -7 and -6, followed by 5 daily doses of fludarabine at 25 mg/m2 on days -5 through -1. Patients then received TIL infusion at doses ranging from 1 x 109 to 150 x 109 on day 0, followed by no more than 6 doses of interleukin-2 (IL-2) at 600,000 IU/kg every 8 to 12 hours. Pembrolizumab was continued at 200 mg every 3 weeks or 400 mg every 6 weeks for up to 2 years.

Concomitant anticancer therapy was not permitted.

The primary end points of the IOV-COM-202 trial were ORR and incidence of grade 3 or higher treatment-emergent adverse effects (TEAEs). Secondary end points included CR rate, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). In C-145-04, the primary end point was incidence of grade 3 or higher TEAEs, and the secondary end points included ORR, DOR, DCR, PFS, and OS.

In cohort 1A of the IOV-COM-202 trial, the median age was 52.0 years (range, 34-68), and 80% of patients were male. These patients received a median number of prior systemic therapies of 0 (range, 0-2). Thirty percent of patients underwent prior chemotherapy, 20.0% of patients received prior BRAF or MEK inhibitors, and 10.0% received prednisone along with a chemotherapy regimen comprised of cyclophosphamide, doxorubicin, and vincristine. The majority of patients had disease metastasis of M1C at study entry (70.0%), followed by M1A (20.0%) and M0 (10.0%). Additionally, 50% of patients were PD-L1 positive, and the median number of target and non-target lesions was 4.0 (range, 2-7).

Patients enrolled to cohort 2A of the IOV-COM-202 trial had a median age was 59.0 years (range, 24-66), and 88.9% of patients were male. This group had received a median number of prior systemic therapies of 1.0 (range, 0-3). Moreover, 66.7% of patients underwent prior chemotherapy, 50.0% had prior radiotherapy, and 11.1% previously received anti-EGFR monoclonal antibody therapy. Most patients had disease metastasis of M1 at study entry (72.2%), followed by M0 (16.7%) and unknown status (11%). Additionally, 61.1% of patients were PD-L1 positive, and the median number of target and non-target lesions was 5.5 (range, 1-8).

Finally, of those included in cohort 3 of the C-145-04 trial, the median age was 46.5 years (range, 37-73). None of these patients received any prior systemic therapies, although 64.3% previously underwent curative or therapeutic surgery, 50.0% received chemoradiotherapy, and 21.4% received radiotherapy alone. Most patients had disease metastasis of M1 at study entry (92.9%), and 1 patient had unknown status. Furthermore, 71.4% of patients were PD-L1 positive, and the median number of target and non-target lesions was 7.0 (range, 1-10).

Among patients in all 3 cohorts (n = 42), 100% experienced at least 1 TEAE of any grade, and 95.2% experienced an effect that was grade 3 or 4 in severity. Additionally, 11.9% of patients experienced a grade 5 TEAE. The most common TEAEs reported across the 3 cohorts were chills (85.7%), pyrexia (78.6%), nausea (78.6%), fatigue (61.9%), hypotension (61.9%), and thrombocytopenia (61.9%).

The TEAE profile across all 3 cohorts was consistent with the underlying disease and known [safety] profiles of pembrolizumab, NMA-LD, and IL-2, according to the press release issued by Iovance Biotherapeutics, Inc.

The combination of TIL and ICIs warrant further investigation in patients with advanced disease, and the IOV-COM-202 and C-145-04 trials are ongoing.

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Addition of TIL Therapy to Pembrolizumab Shows Efficacy in Advanced Melanoma, HNSCC, and Cervical Cancer - OncLive

MELVILLE, N.Y., Dec. 20, 2021 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (the Company" or BioRestorative) (NASDAQ:BRTX), a life sciences company focused on adult stem cell-based therapies, today released the following year-end message.

As we reach the end of 2021, we are inspired by the many healthcare workers and biopharmaceutical companies that have worked to combat the COVID-19 pandemic. This year has been environmentally difficult, but we have seen incredible advancements in our sector which have reinforced the importance of our mission to become a clinical stage company. Since our emergence from Chapter 11 in 2020, we have sought to take positive steps at BioRestorative Therapies with the goal of making it a preeminent cell therapy company. During 2021, we achieved important transformational milestones, which created meaningful intrinsic value and advanced us toward our stated strategic goals.

In November of this year, we closed on a $23 million capital raise and concurrently listed our securities on the Nasdaq Capital Market. This is a very significant development as we are now fully funded to complete our Phase 2 trial for our lead clinical candidate, BRTX-100, for the treatment of chronic lumbar disc disease (CLDD.) During this process, we have attracted many new institutional fundamental investors as well as some retail investors. With that accomplished, I would like to briefly discuss the status of our programs and the opportunities that lie ahead of us.

BRTX-100 is our lead program for the treatment of CLDD, one of the leading causes of lower back pain. Our solution is a one-time injection of 40 million mesenchymal stem cells derived from a patients own bone marrow and expanded ex vivo before re-injection. Two things make us optimistic about this program. First, in connection with our IND filing, we referred the FDA to prior human clinical studies from different institutions that demonstrated the safety/feasibility of using mesenchymal stem cells to treat disc orders. This data not only enabled us to accelerate our clinical program and initiate a Phase 2 trial, but we believe it substantially reduces risk in offering compelling guidance on the use of cell-based interventions to treat lower back pain. Second, our manufacturing of BRTX-100 involves the use of low oxygen conditions, which ensures that the cells have enhanced survivability after introduction into the harsh avascular environment of the injured disc which has little or no blood flow. The benefits of this process are significant and are illustrated well in our recent Journal of Translational Medicine publication. Our approach is akin to transplant medicine in which specific cell types are used to replace the ones which have been lost to disease. We believe that transplanting targeted cells can offer a more attractive safety profile and potentially an improved clinical outcome. We remain optimistic that we will see significant positive clinical outcomes as we proceed with our clinical trial.

The most significant milestones we achieved in 2021 include:

Our 2022 objectives include the initiation of enrollment for our BRTX-100 clinical trial, the development of our overall product profiles via manufacturing and delivery system improvements, and the entering into of technology validation and enabling partnerships to accelerate our clinical timelines.

Some of the events and milestones that we hope to accomplish in 2022 include:

This is an exciting time to be part of the BioRestorative family. As we enter 2022 with a well-capitalized balance sheet to fully fund our Phase 2 trial, we look to accelerate our research and development pipeline. We do not take for granted that our technologies give us an opportunity to make a profound impact on the everyday lives of many people. We are grateful for the opportunity to validate such technologies; it is what we do and what we believe is the center of our core competencies.

Visit our website at http://www.biorestorative.com for more information about BioRestorative.

Thank you to the BioRestorative family for your loyalty and ongoing support.

I wish you and all those near and dear to you a wonderful Holiday Season and the very best for 2022 and beyond.

Very truly yours,

Lance AlstodtPresident, CEO and Chairman of the Board

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Disc/Spine Program (brtxDISC): Our lead cell therapy candidate, BRTX-100, is a product formulated from autologous (or a persons own) cultured mesenchymal stem cells collected from the patients bone marrow. We intend that the product will be used for the non-surgical treatment of painful lumbosacral disc disorders or as a complementary therapeutic to a surgical procedure. The BRTX-100 production process utilizes proprietary technology and involves collecting a patients bone marrow, isolating and culturing stem cells from the bone marrow and cryopreserving the cells. In an outpatient procedure, BRTX-100 is to be injected by a physician into the patients damaged disc. The treatment is intended for patients whose pain has not been alleviated by non-invasive procedures and who potentially face the prospect of surgery. We have received authorization from the Food and Drug Administration to commence a Phase 2 clinical trial using BRTX-100 to treat chronic lower back pain arising from degenerative disc disease.

Metabolic Program (ThermoStem): We are developing a cell-based therapy candidate to target obesity and metabolic disorders using brown adipose (fat) derived stem cells to generate brown adipose tissue (BAT). BAT is intended to mimic naturally occurring brown adipose depots that regulate metabolic homeostasis in humans. Initial preclinical research indicates that increased amounts of brown fat in animals may be responsible for additional caloric burning as well as reduced glucose and lipid levels. Researchers have found that people with higher levels of brown fat may have a reduced risk for obesity and diabetes.

FORWARD-LOOKING STATEMENTS

This letter contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, those set forth in the Company's latest Form 10-K filed with the Securities and Exchange Commission (SEC) and other filings made with the SEC. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this letter are made as of the date hereof and the Company undertakes no obligation to update such statements.

CONTACT:

Email: ir@biorestorative.com

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BioRestorative Therapies, Inc. Releases Year-End Message - BioSpace

After prior data showed that one in four patients with B-cell malignancies did not produce detectable antibodies after receiving their first two doses of the COVID-19 mRNA vaccine, new findings are more promising for these patients.

In results from a larger pool of data presented at the 63rd ASH Annual Meeting, 43% of the patients (109 out of 245) with blood cancers who did not produce antibodies after being administered their first two doses produced antibodies after receiving a third full dose of the mRNA vaccine.

In addition to that, the balance of the patients from 245 up to 699 those 454 patients that were making some antibodies before, after the third vaccination made a very large amount of antibodies in general, up to the maximum amount of antibodies that the assay is capable of detecting. So, they are well protected, said Lee Greenberger, chief scientific officer of the Leukemia & Lymphoma Society (LLS), in an interview with CURE.

Greenberger also pointed out the important distinction here between a COVID-19 booster and a third dose the patients with blood cancer in this study received a third full strength vaccination dose of whatever mRNA vaccine is available to them, rather than a booster dose.

In particular, patients with a blood cancer received the 100-microgram dose of the Moderna vaccine and not the 50-microgram dose that non-immunosuppressed individuals received in the general population. Patients with a blood cancer who received the third dose of the Pfizer vaccine received the same strength as the general population.

Why Patients With B-Cell Malignancies Produce Fewer Antibodies

The researchers, whose data was reported from the LLS National Patient Registry, included a larger number of patients with B-cell malignancies in the study to analyze this population specifically due to their challenges in producing antibodies to prior COVID-19 vaccine doses.

The reason that these patients typically do not see a stimulation of anti-spike antibodies which block entry of COVID-19 into the cells is because their cancer type or their cancer therapy depletes the immune systems B-cells, and these cells are responsible for making antibodies that fight viruses.

So if you don't have a high number of B-cells, or the functionality is suppressed, they won't make antibodies, Greenberger said. And therefore, if you give (them) a vaccine, you just dont make antibodies.

These types of cancers include chronic lymphocytic leukemia (CLL), and some of the most common non-Hodgkin lymphomas: diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma (MCL) and Waldenstrm macroglobulinemia.

However, in patients with other types of blood cancers, including myeloid forms of leukemia, Hodgkin lymphoma and multiple myeloma, detectable antibody rates ranged from 75% to 100%. These cancer types also typically respond favorably to the first two doses of COVID-19 vaccines.

Certain Cancer Treatments May Affect Antibody Production

Treatments such as Bruton tyrosine kinase (BTK) inhibitors, CD19 CAR-T cell therapies and anti-CD20 antibody treatments that deplete B-cells may weaken the immune response to the COVID-19 while a patient is on them, or even for several months after therapy is complete.

There is also a component that the disease itself suppresses B-cell function and that also, even patients who don't have any of those therapies may have impaired B-cell responses and fail to make anti-spike antibodies, Greenberger said.

Of the 320 patients with CLL in the study who are commonly treated with these therapies, 65% of patients who did not receive therapy for two years prior to receiving the vaccine were able to produce antibodies after the third dose. Conversely, patients in this population who did receive these therapies in the last two years had less chance of benefit, with just 23% to 41% producing antibodies post-third dose.

On the other hand, patients who received a certain type of antibody infusion as part of their cancer treatment may obtain an added benefit with the COVID-19 vaccine. Intravenous immunoglobulin (IVIG) infusion, which is typically given to patients on BTK inhibitors, anti-CD20 antibodies or CAR-T cell treatments to replace the lost antibodies, has an increased level of COVID-19 anti-spike antibodies. The reason for this is that IVIG comes from people who donate blood plasma, and many more of the donors are now either vaccinated or have had COVID-19 and thus their plasma contains antibodies.

The LLS study found that some patients treated with this infusion had unusually high levels of antibodies after receiving the third vaccine dose, even among those who had no antibody production after their first two doses.

Patients Should Continue Protective Strategies, Regardless of Vaccination or Antibody Status

Its important for patients with blood cancer to know, Greenberger stressed, that the COVID-19 vaccine is safe for them to receive.

The safety (of the vaccine) is not an issue, he said. You may make anti-spike antibodies to the vaccination, so its important to get them, including the third vaccination.

However, getting the vaccine no matter the dose should not prevent patients from continuing their preventive strategies against the virus.

They should mask up, they should observe distance rules, Greenberger said. And they need to be careful. Particularly patients who have B-cell malignancies, (they) should consider themselves not fully protected, and be careful.

Antibody Cocktails May Help Patients After COVID-19 Exposure

For patients who need to be extra careful about their COVID-19 exposure, Greenberger noted that antibody cocktails may be a helpful option.

Three antibody cocktails and one single antibody are useful to prevent or reduce symptoms of COVID-19 infections. The bamlanivimab and etesevimab antibody cocktail, as well as the casirivimab and indevimab antibody cocktail is used to treat mild to moderate COVID-19.

Both cocktails received additional FDA emergency authorization for use in patients who may be at high risk of progression to severe COVID-19 infections (post-exposure prophylaxis).

The single antibody, Xevudy (sotrovimab), is also FDA-authorized for use in the latter indication.

Recently, the tixagevimab and cilgavimab cocktail received FDA emergency authorization for immunocompromised patients that do not have COVID-19 but are at high risk of poor outcomes if they contract COVID-19 (pre-exposure prophylaxis).

The utility of these antibodies against the Omicron variant is currently under investigation and is likely to be very important in those patients who fail to either make any antibodies or sufficient antibodies after three mRNA vaccinations, according to Greenberger.

In addition, there are studies with fourth vaccinations, he said. Remember that the FDA has basically told patients who are immunosuppressed, after they get the third vaccination, six months later, they should get another vaccination the fourth vaccination, that is an option.

He added that the LLS registry will be following patients who would like to participate and are eligible to receive their fourth dose.

And sometimes it's kind of like starting a car that won't want to start, Greenberger explained. Well, if you try starting it enough, it will eventually start and turn over. And that's what we're hoping for some of these patients who don't make antibodies.

Beyond that, patients who are on therapies with long-lasting B-cell suppressive effects will see these effects eventually time out and their B-cells may be able to start responding to vaccinations again.

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Third Full Dose of COVID-19 Vaccine Increases Antibody Response in Patients with Blood Cancers - Curetoday.com

Apelliss intravitreal formulation of pegcetacoplan targeted C3, and produced a hit and a miss in its twin phase 3 studies, leaving that projects approval prospects in doubt.

Gyroscope recently reported interim data from the phase 1/2 Focus study of GT005, which is delivered via subretinal injection and uses an AAV2 vector. The trial found no serious adverse events among 28 patients, but there was one case of choroidal neovascularisation, which was possibly related to GT005. Apelliss pegcetacoplan was also linked with neovascularisations in phase 2, although this was not so much of an issue in phase 3.

Focus also showed biomarkers going in the desired direction: 11 of 13 evaluable patients had increased complement factor I; all of these 11 had decreases in certain proteins associated with complement activation.

It will now be up to Novartis to prove that this translates into a benefit on geographic atrophy progression. Two phase 2 trials, Explore and Horizon, are ongoing.

Doubling down

Novartis was not the only big pharma to see potential in Gyroscope: Sanofi, another serial acquirer, made a $40m investment in the UK group last month. Other major players are also getting involved in geographic atrophy, with Roche this week striking a small licensing deal with Lineage Cell Therapies.

In many ways, the Gyroscope deal makes sense for Novartis: the group already has a presence in gene therapy and has made no secret of its intention to expand here. In the past year or so it has also picked up the early-stage ocular gene therapy players Vedere Bio and Arctos Medical.

And, with gene therapy price tags depressed, now is probably a good time to buy. But big questions still hang over the field in general, notably around safety, durability and commercial viability.

Even Zolgensma, a relative success story, has not been without its problems, and with US sales flattening the jury is still out on whether the product will justify the $8.7bn that Novartis paid for its developer, Avexis.

In a few years it should become apparent whether Novartiss decision to stick to its gene therapy guns was laudable or just another example of the sunk-cost fallacy.

The undisputed winner from todays takeout is Syncona, Gyroscopes founding investor, which also had a successful exit with Biogens 2019 takeout of another eye gene therapy player, Nightstar. That deal turned out to be a dud, however, and Novartis will have to hope that Gyroscope does better.

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Novartis eyes up another gene therapy - Vantage

Around halfway through 2022, we will have witnessed a number of significant breakthroughs in ways in which we can engineer the bodys immune system to fight disease. The pandemic has already led to the development of new types of vaccine, such as those based on mRNA, and their use will be expanded next year to protect us against other pathogens. But we will also see other ways of harnessing the immune system to fight disease.

One of these will be new types of antibody-based medicine. Antibodies are produced by the body in response to infection and we have worked out ways of using artificially manufactured antibodies to mark cancer cells for destruction. We can also boost the bodys immune cells reactivity against cancer or dampen the immune activity that causes problems in rheumatoid arthritis. Indeed, antibodies are already the basis of seven out of ten of the worlds most profitable medicines.

These antibodies are used in a way which exploits their natural ability to lock onto specific targets. The design of antibodies themselves has been left relatively untouched. In 2022, all that will change.

Now, using genetic engineering or by separating and recombining parts of the protein chemically, we have tools which can alter the basic structure of what an antibody is. These will enable us to produce all manner of antibody-based medicines. For example, we will be able to manufacture antibodies that can recognize and attach to three separate targets at oncemaybe a cancer cell, a receptor protein that activates immune cells, and another immune cell protein that strengthens the response. Already in development is an antibody that can lock onto three different parts of the outside coating of a virus, such as HIV. This should make it harder for the virus to mutate and avoid being targeted.

Another type of immune-based medicine set to gain prominence in 2022 is CAR T-cell therapy. Here, T-cells are extracted from a patients blood and genetically manipulated to endow them with a new receptor that targets the patients own cancer. The engineered T-cells are then infused back, hopefully now able to kill the patients cancer cells. To some extent this type of therapy is already used: some children or young adults with B-cell acute lymphoblastic leukemia have been given CAR T-cell therapy with some striking results, but also unwanted side effects and relapses in some patients. Next year, this type of therapy will expand by using different types of immune cell, or different versions of receptors, and so on. CAR T-cells could be engineered, for example, to kill off a problematic subset of the bodys own immune cells which are causing an autoimmune disease.

Our continuing understanding of the immune system will also enable us to develop new diagnostic tools. Artificial intelligence is already providing us with an unprecedented depth of analysis around immune cells. It is also helping us to correlate their parameters with, for example, the severity of symptoms a person has experienced with coronavirus infection. Next year, we will be able to look for immune signatures that correlate with severe cases of Covid-19 and other diseases, and be able to predict the trajectory of an illness and adjust treatment accordingly. In 2022 and beyond, our increasing knowledge of the immune system will lead to new medicines and new approaches to medicine.

Get more expert predictions for the year ahead. The WIRED World in 2022 features intelligence and need-to-know insights sourced from the smartest minds in the WIRED network. Available now on newsstands, as a digital download, or you can order your copy online.

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Antibodies Are Being Created to Fight Disease in New Ways - WIRED

The Automated And Closed Cell Therapy Processing Systems Market growth is on the back of the increasing popularity of regenerative medicines and cell therapies. In addition to this, various benefits that are provided by the automation technologies for the comprehensive development of therapies are also adding to the market growth.

The rising integration of advanced therapy development procedures and software technologies is also estimated to bring lucrative opportunities to the market. Further, bio manufacturers are investing at a high rate for the development of cellular therapy products with the help of series funding that is anticipated to drive growth impetus in the market in the years to come.

Rising partnerships among different market players for the adoption and application of these systems and increasing product count are also bolstering growth impetus in the market.

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Automated And Closed Cell Therapy Processing Systems Market: Key Trends

Recent years have encountered a massive growth in the clinical trials that are associated with advanced therapies. This market growth has been attributed to the rising demand for advanced and automated technologies. These technologies are used for the achievement of high throughput. This increased growth is possible with various benefits provided by these automated and closed systems. Reduced possibility of errors at the time of bioprocessing and better cell handling abilities are some of the most prominent benefits of these systems. Thus, owing to these factors, the automated and closed cell therapy processing systems market has been expected to grow at a noticeable speed in the forthcoming years.

There has been increased availability of a wide range of systems in the global market. These systems provide automated integrated workflow solutions along with partial automation. In addition to this, these systems also enable constant monitoring of the controlled therapy processing. These initiatives are helpful for the development of various novel therapeutics platforms. Thus, based on these factors, the automated and closed cell therapy processing systems market is experiencing various growth avenues.

Automated And Closed Cell Therapy Processing Systems Market: Competitive Dynamics and Key Developments

The key players serving in the automated and closed cell therapy processing systems market are using different development strategies to drive the growth avenues in the upcoming years. The strategies include mergers and acquisitions, technological partnerships and collaborations, product introductions and approvals, strategic initiatives, and regional expansion that are adopted by these market players to fuel lucrative opportunities in the market.

For instance, Brooks Life Sciences and Cytiva have agreed in order to extend their capabilities of automated cold chain in February 2021. These companies have been working together for the enhancement of capabilities of the automated cold chain system of Cytiva.

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Some key players in the automated and closed cell therapy processing systems market are:

Automated And Closed Cell Therapy Processing Systems Market: Regional Assessment

The automated and closed cell therapy processing systems market has been spread across different geographical locations such as Europe, the Middle East & Africa, North America, Latin America, and Asia Pacific. Out of these areas, the North America region is expected to hold a significant share in the market revenue. The market dominance has been on the back of the rising adoption of the technology for cell therapy processing. In addition to this, rising emphasis on production and high precision is also fueling growth avenues in the market. Furthermore, rising demand for regenerative medicines and growing investments for R & D activities are also bolstering growth impetus in the automated and closed cell therapy processing systems market.

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Automated And Closed Cell Therapy Processing Systems Market is predicted to grow at a noteworthy speed to 2030 | TMR Research Study - BioSpace

NurOwn is being developed for the treatment of amyotrophic lateral sclerosis (ALS), progressive multiple sclerosis (PMS) and other neurodegenerative diseases.

Catalent, a biopharma focused CDMO, entered into a partnership with Brainstorm in 2020 to provide CGMP clinical supply of NurOwn, in anticipation of the product candidate's potential regulatory approval.

Chaim Lebovits, CEO, BrainStorm Cell Therapeutics, said the manufacturing of cellular therapies such as NurOwn is complex and requires careful planning and very specific expertise. He acknowledged the progress made to date through the alliance with Catalent, which it noted has industry-leading capabilities in the field.

The NurOwn technology platform - autologous MSC-NTF cells - represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders, according to BrainStorm.

MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo, it explained.

The MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells are designed to effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

Since 2020, Catalent has invested in its cell therapy capabilities.

Alongside its facility in Texas, it has a site in Maryland, and runs its European Center of Excellence for cell and gene therapy out of its campus in Gosselies, Belgium.

The organization continues to increase its clinical and commercial-scale manufacturing capabilities across the full range of cell and gene therapy activity, with it finalizing a deal to acquire Dusseldorf-based human induced pluripotent stem cells (iPSCs) developer, RheinCell Therapeutics.

John Chiminski, CEO, Catalent, on a conference call with analysts in August, noted that the dynamics in the cell and gene therapy space continue to be extremely robust.

Over the last two years, we've added critical pieces to our portfolio, in the cell therapy space giving additional manufacturing facilities and capacity, we entered into the plasmid DNA space, and now, obviously, with the acquisition of RheinCell, we have our hands on a kind of iPSC cell bank. So, we really think that we have a strong portfolio.

The company, he said, has a strong footprint for cell therapy. And we have a huge capability in viral vector manufacturing in the Baltimore area. But if we were able to get our hands on the right asset from a viral vector manufacturing standpoint in Europe, that would also be a priority for us,added Chiminski.

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Tech transfer box ticked in Catalent and BrainStorm cell therapy alliance - BioPharma-Reporter.com

CAR-T cell therapy, which modifies a patients own T cells to recognize specific antigens on tumors, has proven effective in treating blood cancers. But the engineered immune cells have precious little time to proliferate in the body, which often limits their anti-tumor efficacy. Now, scientists at the Curie Institute in France have identified a potential mechanism that could be targeted to improve T-cell therapies.

By using genomewide CRISPR-Cas9 screen in mice, the Curie Institute team pinpointed the protein SOCS1 as an important brake that inhibits the expansion and survival of CD4+ T cells, according to results published in Science Immunology.

Crippling SOCS1 in human CD19-targeted CAR-T cells markedly improved the persistence of CD4+ CAR-T cells and the function of CD8 CAR-T cells in a mouse model. Thus SOCS1 inhibition could boost the efficacy of T-cell therapies against cancer, the team suggested.

When cancer relapses or progresses after patients initially respond well to CAR-T treatments, the culprit is thought to be poor persistence of the engineered cells. One of the key components of CAR-T cell therapy, CD8+ T cells, can continuously self-proliferate after stimulation. But another critical element, CD4+ T cells, require repeated antigen stimulation to continue growing.

RELATED:Enhancing CAR-T therapy by leveraging its communication with the immune system

To understand the inhibitory mechanism of CD4+ T cells, the Curie Institute team used CRISPR screening to search for genes that, when inactivated, would restore the proliferation of antigen-experienced CD4+ T cells.

The gene encoding for SOSC1 emerged as a hit. In two different TCR CD4+ T-cell models, inactivating the gene helped the T cells expand, while the the proliferation of untreated cells quickly stopped, the researchers reported.

The researchers challenged mice with a type of bladder tumor and treated them with anti-tumor CD4+ T cells. Treatment with T cells that had SOCS1 inactivated rejected the tumors, as the T cells proliferated. The researchers also found that the SOCS1-deleted T cells infiltrated tumors more efficiently than control cells by nearly tenfold.

SOCS1 also played a role in regulating CD8+ T cells, the study found. In mice with melanoma, the scientists observed a significant and durable rejection of tumors in animals that received SOCS1-deleted, tumor-specific CD8+T cells as compared with control T cells.In SOCS1-inactivated T cells that entered tumors, the researchers found higher numbers of cytotoxic molecules and effector T cells, likely explaining the strong anti-tumor effect, they said.

The French team validated their findings with human CD4+ and CD8+ CAR-T cells, reporting that in mouse models of lymphoblastic leukemia, treatment with SOCS1-inactivated CAR-T cells produced better tumor control, and the number of CAR-T cells accumulating in bone marrow was twofold higher than it was with unmodified CAR-T cells.

The promise that engineered T-cell therapy holds against various cancers has prompted scientists across the globe to explore ways to enhance its efficacy. A team at the University of Pennsylvania recently proposed inhibiting BET proteins to prevent T-cell exhaustion in CAR-T cell treatment of chronic lymphocytic leukemia, for example.

Scientists at Frances Pasteur Institute foundthat the interaction between interferon gamma by CAR-T cells and interleukin 12 by host cells is critical to the cancer-killing activity of CAR-T cells. And a team at the Fred Hutchinson Cancer Research Center has designed new CARs with fragments involved in T-cell signaling to increase their ability to recognize tumor antigens.

Read more:
Improving CAR-T cell therapies for cancer by targeting a protein 'brake' - FierceBiotech

Immune checkpoint inhibitors, a type of immunotherapy drug, work well for a specific type of mesothelioma patient.

Another type of immunotherapy treatment, CAR T-cell therapy, seems to cause remission as well.

CAR T-cell therapy, a type of immunotherapy-gene therapy combination, enhances the immune system by modifying T cells to recognize cancer tumors. Those who cant have surgery and people who dont respond to or want chemotherapy are routinely being offered immunotherapy drugs Opdivo and Yervoy, which are approved for mesothelioma officially. CAR T-cell therapy for mesothelioma is still in testing.

Scientists add RNA to T cells removed from the patient. This RNA strand helps T cells connect with a specific protein receptor associated with proteins for a specific cancer, which vary based on the type of malignancy. The added RNA is what makes them CAR T cells.

At the Society for Immunotherapy of Cancer conference, a cell therapy manufacturing company reported disease response in mice with mesothelioma or pancreatic cancer. The manufacturer, Cellectis, hopes the study leads to an off-the-shelf therapy for mesothelin-expressing tumors.

Mesothelin, a protein found in malignant mesothelioma, is a target for specific types of therapy. CAR T cells can be programmed to go link with mesothelin tumors via protein receptors. Cellectis therapy is called UCARTMESO. It also disrupts three genes: TRAC, CD52 and TGFBR2.

The preclinical data demonstrated potent activity of UCARTMESO against mesothelin-expressing cell lines in pancreatic and pleural mesothelioma mouse models, the manufacturers press release reads.

CAR T-cell therapy is already approved for specific blood cancers, such as myeloma and lymphoma. Its currently in testing for solid tumor cancers, such as malignant mesothelioma and others.

Working in mouse models means the next step is running a first-in-patient phase 1 clinical trial. A few studies are already in the works for CAR T-cell therapy for mesothelioma.

Some trials pair T-cell therapy with immune checkpoint inhibitors. Gavo-cel was featured in an MD Anderson Cancer Center clinical trial, which also hunts mesothelin-expressing tumors for mesothelioma cancer. Both proved successful in small sample sizes of patients.

Sources & Author

Devin Golden is the content writer for Mesothelioma Guide. He produces mesothelioma-related content on various mediums, including the Mesothelioma Guide website and social media channels. Devin's objective is to translate complex information regarding mesothelioma into informative, easily absorbable content to help patients and their loved ones.

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CAR T-cell Therapy Shows Signs of Remission for Mesothelioma - Mesothelioma Guide