Monthly Archives: August 2021

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.

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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.

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

Lykan Bioscience, a contract development and manufacturing organization (CDMO) focused on cell-based therapies, and Vineti, which offers a software platform supporting supply chain orchestration for clinical and commercial cell therapies, have entered a partnership to unite Lykans purpose-built cell therapy manufacturing capabilities and Vinetis supply chain and data management system. The partnership empowers biopharma customers with optimized manufacturing efficiency and a complete solution to bring cell-based, life-saving therapies to patients in need.Advanced therapies, such as cell therapies, require advanced infrastructure. Legacy systems managing the production of cell therapies are often manual and outdated, slowing the scale, speed, and patient safety during development. The cell therapy industry requires a new level of visibility, detail, and access across each product and facility within the supply chain. Lykan and Vinetis global, non-exclusive partnership between two leading innovators in the cell therapy space will ensure chain of identity (COI) and chain of custody (COC) visibility as therapies go through each step in the manufacturing supply chain, bringing patient safety back to the forefront.At Lykan, our mission is to be an innovative manufacturer of cell therapy products. We strive to help our biopharma partners achieve a rapid transition from clinical to commercial manufacturing and maximize patient access to cell therapies. The complex nature of cell therapy process development and manufacturing means our partners need innovative technologies, a reliable platform and strong manufacturing expertise to deliver safe and effective therapies, said Patrick Lucy, president and CEO, Lykan. Our strategic partnership with Vineti aims to enable our partners success with faster and simpler operations using a more robust and traceable control system.Lykan Bioscience has established a world-class, purpose-built, multi-product cell therapy manufacturing facility just outside of Boston, MA. Advanced and integrated software systems, such as Vinetis Personalized Therapy Management (PTM) platform, a proven purpose-built, enterprise-grade digital solution for advanced therapy data and supply chains, will enable Lykan to conduct real-time monitoring of the manufacturing process and product, complete with electronic batch records that will support real-time testing and release of product from each of Lykans eight clinical and commercial cGMP manufacturing suites.Amy DuRoss, CEO of Vineti, said, Cell therapies are at a point where they require a truly world-class, purpose-built, multi-product cell therapy manufacturing facility, with the best digital tools, allowing for true connectivity across the ecosystem. We are thrilled to partner with Lykan Bioscience to ensure COI and COC visibility as therapies go through each step in the supply chain, to efficiently deliver these therapies to the patients that need them faster."This partnership follows Lykans recent announcement on the hiring of the companys new CTO and Vinetis release of its PTM Essentials solution for clinical-phase advanced therapies. More information on the Lykan-Vineti solution is available through both companys business development teams.

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Lykan And Vineti Form Cell Therapy Agreement - Contract Pharma

In a preclinical study, researchers were able to show that their modified adeno-associated virus (AAV) vector safely delivered the chimeric antigen receptor (CAR) gene into the host cells and produced enough CAR T cells to cause effective tumor regression and elicit antitumor immunological characteristics in a mouse model of human T-cell leukemia.

Recently published findings are documenting a novel approach that researchers say may make chimeric antigen receptor (CAR) T-cell therapy for leukemia simpler and less expensive because it doesnt require patient lymphodepletion or the processes of current CAR T-cell production. The approach allows the patient to generate CAR T cells by injecting an adeno-associated virus (AAV) vector that supplies the CAR gene.

In the current study, researchers were able to show that their modified AAV vector safely delivered the CAR gene into the host cells and produced enough CAR T cells to cause effective tumor regression and elicit antitumor immunological characteristics in a mouse model of human T-cell leukemia. Notably, this response was observed after a single infusion and the generated CAR T cells circulated the host body for weeks, able to detect and attack the target cells.

To the best of our knowledge, this is the first report describing that an AAV carrying a CAR gene can reprogram immune cells in vivo to generate enough CAR T cells to induce tumor regression, reflected the researchers. Our current CAR gene-carrying AAV strategy contrasts with the costly and time-consuming method of conventional manufacturing CAR T therapy, which requires primary T-cell isolation and transgene introduction and expansion via lentiviral vectors or retroviral vectors ex vivo.

According to the researchers, AAV has been a popular method and is being extensively studied for therapeutic gene delivery, often being leveraged to carry genetic material into the target cells to cure or treat a disease.

For the study, the researchers chose CD4-targeting CAR due to the aggressive nature of CD4+ leukemia and lymphoma, which often dont respond to chemotherapy.

Initial preclinical studies of CAR T cells for targeting CD4+ tumors are encouraging, but to date, no standard care has been developed, explained the group. Furthermore, CD4 + cells are the major latent reservoir of HIV, posing a challenge for HIV eradication; therapies targeting CD4+ cells can also be translated into HIV treatment and treatments for other infectious diseases, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and psoriasis.

The researchers noted that there was a complete CD4+ depletion in the mice, which raises concerns about the possible effects in the long term or clinical setting, as long-term CD4 helper T-cell depletion can cause on-target, off-tumor toxicities and immunodeficiency.

Reference

Nawaz W, Huang B, Xu S, et al. AAV-mediated in vivo CAR gene therapy for targeting human T-cell leukemia. Blood Cancer J. 2021;11(6):119. doi:10.1038/s41408-021-00508-1

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Researchers Highlight Delivery of CAR T-Cell Therapy Through Modified AAV - AJMC.com Managed Markets Network