CAR T–Cell Therapies have been recently been abuzz with announcements of progressive developments from multiple companies. CAR T–Cell therapy uses the patient’s own T cells by separating them from the blood and lymphocytes in White Blood Cells (WBC). These T cells then are genetically engineered with disabled virus and instructions to grow a receptor called Chimeric Antigen Receptor (CAR) which would be allowed to multiply in millions before being administered back into the patient. Their receptors allow the identification of cancer cells in the body and guide the immune system to destroy them. CAR T Cell Therapy has been approved for aggressive or recurring forms of cancer like non-Hodgkin lymphoma and rare forms of Leukemia.
Gilead held Kite Pharma became the latest to receive US Food and Drug Administration’s (FDA) accelerated approval for its CAR-T therapy Tecartus. This approval marks Kite’s second approved CAR T–cell therapy and is the only company to boast of two approved CAR T-cell therapies in the market. The therapy underwent an accelerated approval and was granted a Breakthrough Therapy Designation as it is the only CAR-T cell therapy for relapsed or refractory mantle cell lymphoma (MCL) in adult patients. The approval is based on Phase II ZUMA-2 Trial results which were published in The New England Journal of Medicine. Of the 74 participants in the trial, 87% responded to a single infusion of the therapy and 62% of patients showed complete response to the therapy as per the Lugano classification, which essentially denotes that complete disappearance of all cancer lesions. The current treatment regime for mantle cell lymphoma includes intravenous chemotherapy along with rituximab and in cases of relapsed cancer proteasome inhibitors like Bortezomib and BTK (Bruton’s Tyrosine Kinase) inhibitors like Ibrutinib®) are administered. Compared to the current long-term treatment options, this cell therapy requires a single infusion.
Though both Tecartus and Yescarta target CD-19 T cells, Tecartus’ manufacturing process has been tweaked to target this rare form of B-cell lymphoma. This uses the XLP™ manufacturing process that involves a lymphocytes enrichment and T-cell selection which is critical for B-cell malignancies specific to mantle cell lymphoma. The median turn-around time observed from leukapheresis to final therapy product is 15 days, which is by far the quickest as observed for commercial CAR T-cell therapies when compared to Kymriah which has a turn-around time of 22 days and 26 to 29 days for Yescarta. This quick manufacturing speed is critical for patients with advanced disease where disease progression can be very quick and timely intervention is a life-saver.
Bristol Myers Squibb also announced that the European Medicines agency (EMA) validated its investigational CAR T– Cell therapy Lisocabtagene Maraleucel’s (liso-cel) Market Authorization Application (maa) for the treatment of adults with primary mediastinal B-cell lymphoma (PMBCL), relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3B (FL3B) after at least two prior therapies. The basis of the application was a multicenter pivotal phase I study TRANSCEND NHL 001 and a multicenter Phase II Study TRANSCEND WORLD conducted in Europe and Japan. It previously received access to the PRIME scheme – an EMA initiative to support development to therapies targeting diseases with unmet needs and has now received Accelerated Assessment status reducing the maximum timeframe to 150 days for EMA’s committee to review the application.
Another promising development was Novartis’ announcement that its CAR T–cell therapy Kymriah® (tisagenlecleucel) showed promising results in patients with relapsed or refractory (r/r) follicular lymphoma (FL) as it met its primary endpoint measures in Phase II ELARA Trial. Kymriah was the first approved CAR T– Cell therapy and has two prior indications for the treatment of r/r pediatric and young adult (up to 25 years of age) acute lymphoblastic leukemia (ALL), and r/r adult diffuse large B-cell lymphoma (DLBCL). Regulatory filings in US and EU are expected in 2021 and once approved, it will become the only CAR-T therapy with three approved indications. Novartis continues to ramp up its manufacturing capacity in anticipation of greater demand for its CAR-T therapy, EMA recently approved two additional commercial manufacturing facilities of Novartis in France and Stein.
The rapid pace of development and the expanding scope of CAR T–therapies points towards a promising future ahead for commercial cell therapies. While CAR T-cell therapy can offer unprecedented life-saving results with a single administration, their high cost has been a bottleneck in the widespread adoption of the same. Debates around reimbursement models around next-generation therapies with high-price tags continue to abound with the need to make these therapies more cost-effective and price-friendly which could entail certain upstream and downstream process optimizations to bring down the overall cost of production. We are hopeful that the as the market for CAR T–therapies mature, these challenges will be addressed with greater confidence from all stakeholders involved.