▎Edited by the WuXi AppTec content team

Recently, the global cell and gene therapy (CGT) field has seen a series of advancements. Adaptimune Therapeutics announced that the U.S. FDA has accepted the Biologics License Application (BLA) for its T-cell receptor (TCR)-T cell therapy, afami-cel.Priority Review Status, if approved, will becomeThe First TCR-T Cell Therapy for Solid Tumors. The IND applications for the CAR-T therapies being developed by Oricell Therapeutics and Gracell have been approved by the U.S. FDA. This article will provide a brief introduction to some of the key advancements, for readers' reference only.

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———✦R&DProgress✦———

◇Adaptimune Therapeutics announced that the U.S. FDA has accepted the Biologics License Application (BLA) for its investigational engineered T-cell therapy, afami-cel, and granted it Priority Review. The press release noted that if approved,Afami-cel will become the first engineered T-cell therapy for the treatment of solid tumors, as well as the first effective therapy for synovial sarcoma in more than a decade.

Afami-cel is an engineered TCR-T cell therapy targeting the MAGE A4 cancer antigen.The submission of this BLA is based on positive data from Cohort 1 of the pivotal study SPEARHEAD-1. The study met its primary efficacy endpoint.The overall response rate (ORR) of patients was approximately 39%, with a median duration of response of about 12 months.Historically, the median overall survival (OS) for synovial sarcoma patients who have received two or more prior therapies is less than 12 months, whereas the median OS for patients treated with afami-cel is approximately 17 months, surpassing historical control data. Among advanced synovial sarcoma patients who responded to afami-cel treatment, 70% were still alive two years post-treatment.

◇Jaguar Gene Therapy Announces FDA Approval of IND Application for JAG201, a Gene Therapy for the Treatment of Inherited Autism Spectrum Disorder (ASD) and Phelan-McDermid Syndrome (PMS)JAG201 is designed for delivery via the AAV9 vector.SHANK3A functional copy of the gene permanently restores synaptic function required for learning and memory, fundamentally treating ASD and PMS.Preclinical studies in rodents and non-human primates have shown that the delivery of functionalSHANK3May improve behavioral, cognitive, and motor function abnormalities. The company plans to initiate a Phase 1 trial in the United States in the second half of 2024, targeting adult patients with ASD or PMS who have SHANK3 mutations or deletions.

◇Kiromic BioPharma Announces Positive Preliminary Data from Phase 1 Clinical Trial of Its Investigational γ-δ T Cell (GDT) Therapy Deltacel for the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC), Demonstrating Promising Early Efficacy in the First Patient.Deltacel is an allogeneic cell therapy composed of unmodified GDT. Deltacel aims to leverage the natural potency of GDT to target solid tumors, with the initial clinical development focus on NSCLC.Data from two preclinical studies indicate that Deltacel, when combined with low-dose radiation therapy, demonstrates favorable safety and efficacy.

The first patient was diagnosed as having active disease progression three days before the start of treatment.After six weeks of Deltacel treatment, CT scans confirmed stable disease in this patient, with an initial progression-free survival of one and a half months.。

◇Caribou Biosciences recently announced in the Proceedings of the National Academy of Sciences (PNAS) published a research paper on the company's fully human BCMA-targeted CAR-T therapy, Idecabtagene Vicleucel Injection (research code CT103A), for the treatment of Immune-Mediated Necrotizing Myopathy (IMNM),Preliminary results have demonstrated the good tolerability and safety of BCMA-targeted CAR-T therapy in IMNM, its durable pathogenic antibody clearance effect, and potential long-lasting clinical efficacy, providing a novel therapeutic approach for antibody-mediated autoimmune diseases.

◇Biosyngen Announces BST02 Granted Fast Track Designation by U.S. FDA for the Treatment of All Liver Cancer Types, Including Hepatocellular Carcinoma and Cholangiocarcinoma

BST02 therapy is a T-cell treatment product based on the expansion of patients' own tumor-infiltrating lymphocytes (TIL)., which belongs to adoptive immune cell therapy technology. Previously, this therapy has been approved by the FDA to conduct Phase 1/2 clinical trials, and in January this year, it also received implied permission for clinical trials from the Center for Drug Evaluation (CDE) of China's National Medical Products Administration. The press release noted that this isThe world's first liver cancer TIL therapy to enter clinical development.

OriCAR-017 Demonstrates Robust and Durable Antitumor Efficacy Along with Excellent Safety in Early Exploratory Clinical Studies

◇Gracell Bio Announces FDA Approval of Another IND Application for FasTCAR-T GC012F, Permitting the Initiation of a Phase 1 Clinical Trial in the U.S. to Evaluate GC012F as an Early-Line Treatment for Multiple Myeloma (ELMM).GC012F is a BCMA and CD19 dual-target autologous CAR-T candidate product.。

At the 65th American Society of Hematology Annual Meeting held in December 2023, Gracell announced the latest research results of GC012F in treating newly diagnosed multiple myeloma patients. The data showed: an overall response rate of 100%, and a stringent complete response rate with minimal residual disease negativity (MRD-sCR) as high as 95.5%.

◇Kite, a Gilead Sciences company, announced that the U.S. FDA has approved its updated CAR-T cell manufacturing process.Reduced the median turnaround time (TAT) for its CAR-T therapy Yescarta (axicabtagene ciloleucel) from 16 days to 14 days.The median TAT is defined as the time from the initiation of leukapheresis for collecting the patient’s T cells to the completion of product manufacturing, making it ready for patient infusion. The press release noted that for critically ill patients, every day is precious, and shortening the production time of CAR-T therapy can offer patients the best chance of survival.

◇Kyverna stated in its filing with regulatory authorities that it plans to raise $182 million through an IPO.Kyverna Aims to Combine T-cell Engineering and Synthetic Biology Technologies to Develop Regulatory T Cell (Tregs) Therapies, Allogeneic/Autologous CAR-T Cell Therapies for the Treatment of a Wide Range of Autoimmune and Inflammatory Diseases.

The company's leading investigational therapy, KYV-101, is an autologous, fully human CD19-targeted CAR-T cell therapy designed for the treatment of B-cell-driven autoimmune diseases. The chimeric antigen receptor in KYV-101 was designed by the National Institutes of Health (NIH) to enhance tolerability. This therapy was previously evaluated in a Phase 1 trial involving 20 patients with B-cell lymphoma, and analysis showed that 55% of patients achieved complete remission. Patients receiving this therapy exhibited low levels of cytokines in their blood, with only 5% experiencing severe nephrotoxicity.

Kyverna is currently conducting trials of KYV-101 in patients with lupus nephritis, an autoimmune disease where more than half of the patients do not achieve complete remission with current therapies and are at risk of developing kidney failure.KYV-101 was recently granted Fast Track designation by the U.S. FDA for the treatment of myasthenia gravis and multiple sclerosis.

◇Regeneron Pharmaceuticals announced the establishment based on its agreement with 2seventy bio.Regeneron Cell Medicines, and acquire all development and commercialization rights to 2seventy bio's novel immunocyte therapy research pipeline, as well as its drug discovery and clinical production capabilities. The 2seventy bio employees supporting the acquired projects will join Regeneron Cell Medicines—a newly established R&D division aimed at advancing the development of cell therapies and combination therapies in the fields of oncology and immunology.

◇Fractyl Health Announces $110 Million IPO, Surpassing Previous Expectation of $99 Million. Fractyl Health is dedicated to developing innovative therapies for type 2 diabetes and obesity. The company’s pipeline includes a gene therapy that expresses GLP-1 receptor agonists in the pancreas, which has the potential to help obese patients maintain weight loss without the need for long-term GLP-1 receptor agonist treatment.

Previously published preclinical study results showed that in rodent obesity models, a single infusion of the company's developed gene therapy GLP-1 PGTx reduced mice's weight by 27% after 28 days, while the control group continuously treated with semaglutide (10 nmol/kg/day) experienced a 21% weight reduction during the same period. This difference was statistically significant. These findings suggest that targeted delivery of GLP-1 PGTx can achieve lasting weight loss in obese animals with just one administration.

———✦Regulatory Updates✦———

◇The U.S. FDA recently released twoFinal Version Guidelines Document, aiming to assist the industry in developing gene therapies using genomic editing and CAR-T cell products manufactured in vitro.

A 19-page genome editing guideline document clarifies the FDA's position on supporting the development of genome editing therapies through the accelerated approval pathway.In the guidelines, the FDA wrote: "The FDA supports the use of an accelerated approval pathway for genomic editing products and encourages developers to discuss the possibility of using this pathway for products under research as early as possible, including discussions in the early stages of clinical development, providing alternative endpoints or intermediate clinical endpoints."

FDA Guidelines on Genomic Editing Therapies Include the Agency's Considerations on the Therapy’s Chemistry, Manufacturing, and Controls (CMC), Preclinical Studies, and Multiple Aspects of Clinical Trials.

The final version of the guideline document provides specific recommendations on CMC, pharmacology and toxicology, and clinical trial design for CAR-T cell therapy. Compared with the previous draft guidelines, the final version adds a focus on cancer indications, as well as detailed suggestions regarding the potency, stability studies, and clinical monitoring of CAR-T cells expressing multiple transgenic components. Although this guideline specifically targets CAR-T therapy, the FDA also noted that some of the information and recommendations may be applicable to other genetically engineered lymphocyte products, such as CAR-NK cells or T-cell receptor-modified T cells.

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References:

[1] Groundbreaking genome editing tools unlock new possibilities for precision medicine. Retrieved February 1, 2024, from https://www.eurekalert.org/news-releases/1032950

[2] Jaguar Gene Therapy Announces FDA Clearance of IND to Study JAG201 in a Genetic Form of Autism Spectrum Disorder and Phelan-McDermid Syndrome. Retrieved February 1, 2024, from https://www.businesswire.com/news/home/20240131087815/en

[3] FDA finalizes CAR-T and gene therapy guidance, offers support for accelerated approvals. Retrieved February 1, 2024, from https://endpts.com/fda-finalizes-car-t-and-gene-therapy-guidance-offers-support-for-accelerated-approvals/

[4] FRACTYL HEALTH ANNOUNCES PRICING OF INITIAL PUBLIC OFFERING, from https://ir.fractyl.com/news-releases/news-release-details/fractyl-health-announces-pricing-initial-public-offering 

[5] Kyverna seeks $182M IPO as biotech runs multiple autoimmune CAR-T trials. Retrieved February 1, 2024, from https://endpts.com/kyverna-seeks-182m-ipo-as-biotech-runs-multiple-autoimmune-car-t-trials/

[6] Biosyngen Announces FDA Fast Track Designation for BST02 in Treatment of Liver Cancer. Retrieved February 1, 2024, from https://www.prnewswire.com/news-releases/biosyngen-announces-fda-fast-track-designation-for-bst02-in-treatment-of-liver-cancer-302050377.html

[7] Atara Biotherapeutics and Pierre Fabre Laboratories Announce Publication of Phase 3 ALLELE Tab-cel® Data in The Lancet Oncology. Retrieved February 1, 2024, from https://www.businesswire.com/news/home/20240131800324/en

[8] Gracell's Idecabtagene Vicleucel Injection Globally First Used for Treating IMNM Research Published in PNAS. Retrieved February 1, 2024, from https://www.prnasia.com/story/435594-1.shtml

[9] Kite Receives U.S. FDA Approval of Manufacturing Process Change Resulting in Reduced Median Turnaround Time for Yescarta® CAR T-cell Therapy. Retrieved February 1, 2024, from https://www.businesswire.com/news/home/20240121113292/en

[10] Regeneron Announces Formation of Regeneron Cell Medicines with the Acquisition of 2seventy bio Platforms and Preclinical and Clinical Programs. Retrieved February 1, 2024, from https://www.globenewswire.com/news-release/2024/01/30/2819810/0/en/Regeneron-Announces-Formation-of-Regeneron-Cell-Medicines-with-the-Acquisition-of-2seventy-bio-Platforms-and-Preclinical-and-Clinical-Programs.html

[11] Regulatory Applications Accepted in the U.S. and Japan for Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel) in Relapsed or Refractory Follicular Lymphoma (FL) and Relapsed or Refractory Mantle Cell Lymphoma (MCL). Retrieved February 1, 2024, from https://www.businesswire.com/news/home/20240129726220/en

[12] Oricell Announces FDA Clearance of IND Application for OriCAR-017, a novel GPRC5D Targeted CAR-T Cell Therapy Utilizing the Company's Proprietary Platform, for the Treatment of Relapsed/Refractory Multiple Myeloma. Retrieved February 1, 2024, from https://www.prnewswire.com/news-releases/oricell-announces-fda-clearance-of-ind-application-for-oricar-017-a-novel-gprc5d-targeted-car-t-cell-therapy-utilizing-the-companys-proprietary-platform-for-the-treatment-of-relapsedrefractory-multiple-myeloma-302046662.html

[13] Kiromic BioPharma Reports Favorable Early Efficacy Results from First Patient in Deltacel-01 Phase 1 Clinical Trial in Non-Small Cell Lung Cancer. Retrieved February 1, 2024, from https://www.businesswire.com/news/home/20240129301996/en

[14] Gracell Biotechnologies Announces FDA Clearance of IND Application for Phase 1 Clinical Trial of FasTCAR-T GC012F as Early-Line Treatment of Multiple Myeloma. Retrieved February 1, 2024, from https://www.globenewswire.com/news-release/2024/01/29/2818728/0/en/Gracell-Biotechnologies-Announces-FDA-Clearance-of-IND-Application-for-Phase-1-Clinical-Trial-of-FasTCAR-T-GC012F-as-Early-Line-Treatment-of-Multiple-Myeloma.html

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