CAR-T Moves to First-Line Therapy as Protein Degraders and Off-the-Shelf Cell Therapies Show Promising Advances

The 63rd American Society of Hematology (ASH) Annual Meeting, which opened the other day, is a grand event in the hematology field where biopharmaceutical and technology companies share their latest R&D results. Today, the content team of WuXi AppTec will continue to share the latest trial results of CAR-T therapy, protein degradation therapy, off-the-shelf cell therapy, and innovative targeted therapies.

78% Complete Remission Rate: First CAR-T Frontline Treatment Clinical Results Announced

Today, Kite, a subsidiary of Gilead Sciences, announced clinical trial results for the CAR-T therapy Yescarta (axicabtagene ciloleucel) as part of a first-line treatment regimen for patients with high-risk large B-cell lymphoma (LBCL). The press release noted that this is the first study to evaluate first-line CAR-T treatment in high-risk LBCL patients.

The test results showed that, after a single infusion of Yescarta, at a median follow-up time of 15.9 months, 89% of evaluable patients (n=37) achieved remission, with 78% achieving complete remission. As of the data cutoff date, 73% of patients still maintained sustained remission, and the median duration of response, event-free survival, and progression-free survival had not yet been reached. The estimated event-free survival rate at 12 months was 73%, the progression-free survival rate was 75%, and the overall survival rate was 91%.

"The high and sustained remission data achieved with a single infusion of Yescarta in high-risk LBCL patients is remarkable," said Dr. Frank Neumann, Head of Global Clinical Development at Kite. "We need further research to understand the potential of Yescarta as a first-line therapy, but these results are encouraging."

83% of Patients Achieve Stringent Complete Response, Janssen/Legend Biotech CAR-T Therapy Shows Impressive Long-Term Efficacy

Janssen Pharmaceuticals Announces Latest Clinical Trial Results for CAR-T Therapy Ciltacabtagene Autoleucel (Cilta-Cel) Co-Developed with Legend Biotech. The trial results show that cilta-cel demonstrated durable anti-cancer activity in patients with relapsed/refractory multiple myeloma who had received multiple prior therapies. At a median follow-up time of 22 months, 83% of patients achieved stringent complete response, an improvement from 80% at a median follow-up time of 18 months.

Cilta-cel is a CAR-T therapy targeting B-cell maturation antigen (BCMA) jointly developed by Janssen and Legend Biotech. It carries two antibody-binding domains that bind to BCMA. Currently, it is under regulatory review by the U.S. FDA and is expected to gain approval by next spring.

▲Schematic diagram of Cilta-cel (also known as JNJ-4528/LCAR-B38M) (Image source: Legend Biotech's official website)

At a median follow-up time of 22 months, neither the median progression-free survival nor the median overall survival had been reached, indicating the long-term durability of patient responses. Among 61 patients evaluable for minimal residual disease (MRD), 92% achieved MRD negativity. In patients maintaining MRD negativity for over 6 months, the two-year progression-free survival rate was 91%, and in those maintaining MRD negativity for over 12 months, the two-year progression-free survival rate was 100%.

"Typically, patients whose disease progresses after receiving three prior lines of therapy have a median survival of less than one year," said Dr. Thomas Martin, the principal investigator of this clinical trial. "Data presented at the ASH Annual Meeting showed that a single infusion of cilta-cel can produce durable responses and long-term survival in patients, further demonstrating its potential as a new treatment option."

STAT3, BTK Protein Degradation Therapy Shows Anti-Cancer Potential

Kymera Therapeutics Announces Preclinical Results of Its Potential "First-in-Class" STAT3-Targeted Protein Degrader KT-333. This innovative protein degrader has already received FDA approval in the United States and is about to enter human clinical trials.

Preclinical results presented at the ASH Annual Meeting show that KT-333 induces tumor cell growth arrest and cell death in multiple anaplastic large cell lymphoma (ALCL) models. KT-333 reduces STAT3 levels by more than 90% and modulates STAT3-dependent signaling pathways.

Moreover, KT-333 reduces the expression of factors mediating immunosuppression in an in vitro cell culture model of the non-small cell lung cancer tumor microenvironment.

Nurix Therapeutics Presents Preclinical Data for NX-5948, an Oral BTK Degrader that Crosses the Blood-Brain BarrierNurix Therapeutics announced preclinical results for its oral Bruton’s Tyrosine Kinase (BTK) degrader NX-5948. NX-5948 is a targeted protein degrader capable of crossing the blood-brain barrier and reducing BTK levels in brain tumor cells and microglia.

▲NX-5948 significantly reduces BTK protein levels in TMD8 tumor cells and microglia in the brain (Image source: Nurix company website)

In mouse models, NX-5948 significantly reduced tumor burden in the animals' brains and extended their lifespan.

▲NX-5948 Reduces Intracranial TMD8 Tumor Burden and Extends Animal Survival (Image Source: Nurix Official Website)

Nurix Therapeutics has received approval from UK regulatory authorities to initiate a Phase 1 clinical trial in the first half of next year, testing the efficacy and safety of NX-5948 in patients with relapsed/refractory B-cell malignancies.

Positive Clinical Results for Multiple Ready-to-Use Cell Therapies

Developing allogeneic cell therapies using cells obtained from healthy volunteers can provide off-the-shelf treatment options for cancer patients, increasing their access to cell-based therapies. At the ASH Annual Meeting, several biotech companies presented the latest clinical trial results of various off-the-shelf cell therapies.

One of the major challenges with off-the-shelf cell therapies is that the infused cells may attack the patient’s healthy tissues, leading to graft-versus-host disease (GVHD). Tessa Therapeutics addresses this challenge by utilizing virus-specific T cells (VSTs), which are produced when the body is infected with a virus. These cells can recognize virus-infected cells and trigger a coordinated immune response. An important characteristic of allogeneic VSTs is their high safety profile, as they carry a low risk of immune rejection and causing GVHD in patients.

The company's CD30-targeted CAR-T therapy, CD30.CAR EBVST, expresses a chimeric antigen receptor (CAR) targeting the CD30 antigen on EBV-specific T cells, directing them to specifically kill lymphoma cells expressing CD30.

▲Mechanism of Action of CD30.CAR EBVST (Image Source: Tessa Therapeutics official website)

Results presented at the ASH Annual Meeting showed that among nine patients treated with three different doses of CD30.CAR EBVST, seven (77.8%) achieved remission, including four complete responses and three partial responses. All three patients who received the highest dose achieved complete remission.

This therapy also demonstrated good safety, with no dose-limiting toxicity, no GVHD, neurotoxicity, or cytokine release syndrome of grade 3 or higher observed.

Fate Therapeutics Presents Updated Results from First-of-Kind NK Cell Cancer Immunotherapy Derived from iPSCsFate Therapeutics has announced the latest results of FT516, an off-the-shelf natural killer (NK) cell therapy derived from induced pluripotent stem cells (iPSCs). This NK cell therapy expresses a novel high-affinity CD16 (hnCD16) Fc receptor on its surface, which, when used in combination with antibody therapies, can further enhance antibody-dependent cellular cytotoxicity (ADCC).

▲Design of FT516 (Image Source: Fate Therapeutics official website)

Latest clinical trial results show that at a median follow-up time of 9.1 months, out of 10 patients who had not previously received autologous CAR-T therapy, 6 patients remained in remission after receiving FT516 treatment.

At a median follow-up of 6.5 months, 3 of 8 patients who had previously received autologous CAR-T therapy remained in remission after treatment with FT516. Specific trial data are shown in the table below:

Image Source: Fate Therapeutics Official Website

Fate Therapeutics Announces FT516 Granted Regenerative Medicine Advanced Therapy Designation by U.S. FDA for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Allogene Therapeutics announced the Phase 1 clinical trial results of its off-the-shelf BCMA-targeted CAR-T therapy, ALLO-715. As of October 14, 2021, 43 patients with relapsed/refractory multiple myeloma received treatment with ALLO-715. In the subgroup of patients (n=24) who received a lymphodepletion regimen consisting of fludarabine, cyclophosphamide, and the anti-CD52 antibody ALLO-647 followed by a dose of 320 x 10^6 CAR-T cells, the objective response rate was 71%, with 46% of patients achieving very good partial response and 25% achieving complete response or stringent complete response.

Innovative Targeted Therapy Offers New Options for Leukemia Patients

Loxo Oncology, a subsidiary of Eli Lilly, announced the latest clinical trial results for pirtobrutinib, a non-covalent selective BTK inhibitor, in treating patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL).

Among 296 patients with CLL/SLL, 252 were evaluable for efficacy. Pirtobrutinib achieved an overall response rate (ORR) of 68%. Responses deepened over time, and in patients with more than 12 months of follow-up, the ORR increased to 73%.

Among 100 MCL patients who had previously been treated with a BTK inhibitor, the ORR was 51%. Among 11 MCL patients who had not been treated with a BTK inhibitor, the ORR was 82%.

Novartis announced the latest results of a phase 3 clinical trial for its ABL1 allosteric inhibitor Scemblix (asciminib) in treating Philadelphia (Ph) chromosome-positive CML patients in the chronic phase who have been previously treated. Scemblix is the first CML therapy to bind to the myristoyl pocket of ABL1, offering an important new treatment option for patients resistant or intolerant to current tyrosine kinase inhibitor therapies.

At a follow-up time of 48 weeks, the major molecular response rate in the Scemblix group was 29.3%, twice that of the active control group (13.2%). Moreover, the proportion of patients discontinuing treatment due to adverse events in the Scemblix group was one-third of that in the active control group (7.1% vs. 25%).

We look forward to the smooth progress of the clinical development of these innovative therapies, bringing more treatment options to patients with blood disorders.

References:

[1] Janssen Presents Updated Results Evaluating First-in-Class Talquetamab (GPRC5DxCD3 Bispecific Antibody) in Heavily Pretreated Patients with Multiple Myeloma. Retrieved December 13, 2021, from https://www.janssen.com/janssen-presents-updated-results-evaluating-first-class-talquetamab-gprc5dxcd3-bispecific-antibody

[2] New Data from CARTITUDE-1 Study Show Continued Deep and Durable Responses of Ciltacabtagene Autoleucel (cilta-cel) in Treatment of Heavily Pretreated Patients with Multiple Myeloma. Retrieved December 13, 2021, from https://www.janssen.com/new-data-cartitude-1-study-show-continued-deep-and-durable-responses-ciltacabtagene-autoleucel-cilta

[3] Kymera Therapeutics Presents Positive Preclinical Data on Selective STAT3 Degraders for Hematological and Solid Tumor Malignancies at 63rd American Society of Hematology (ASH) Annual Meeting. Retrieved December 13, 2021, from https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-presents-positive-preclinical-data-selective

[4] NX‑5948, a Selective Degrader of BTK With Activity in Preclinical Models of Hematologic and Brain Malignancies. Retrieved December 13, 2021, from https://ir.nurixtx.com/static-files/4b347182-b738-4dce-87ec-b665486fe95b

[5] Tessa Therapeutics Showcases Positive Clinical Data from Phase 1 Study of “Off the Shelf” CD30 Cell Therapy at 2021 Annual Meeting of American Society of Hematology (ASH). Retrieved December 13, 2021, from https://www.tessacell.com/2021/12/12/tessa-therapeutics-showcases-positive-clinical-data-from-phase-1-study-of-off-the-shelf-cd30-cell-therapy-at-2021-annual-meeting-of-american-society-of-hematology-ash/

[6] Fate Therapeutics Highlights Positive Durability of Response Data from FT516 Phase 1 Study for B-cell Lymphoma and Announces FDA Regenerative Medicine Advanced Therapy Designation Granted to FT516 for Relapsed / Refractory DLBCL. Retrieved December 13, 2021, from https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-highlights-positive-durability-response-data

[7] Allogene Therapeutics Reports Positive Results from Phase 1 UNIVERSAL Study of Single Dose ALLO-715 AlloCAR T™ Cell Therapy in Relapsed/Refractory Multiple Myeloma at the 63rd American Society of Hematology Annual Meeting. Retrieved December 13, 2021, from https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-reports-positive-results-phase-1-universal

[8] Loxo Oncology at Lilly Announces Updated Data from the Phase 1/2 BRUIN Clinical Trial for Pirtobrutinib at the American Society of Hematology Annual Meeting. Retrieved December 13, 2021, from https://investor.lilly.com/news-releases/news-release-details/loxo-oncology-lilly-announces-updated-data-phase-12-bruin-1

[9] Novartis Scemblix® demonstrates sustained response rate in 48-week follow-up in patients with chronic myeloid leukemia. Retrieved December 13, 2021, from https://www.novartis.com/news/media-releases/novartis-scemblix-demonstrates-sustained-response-rate-48-week-follow-patients-chronic-myeloid-leukemia

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