Blog September 20, 2017

Advances and Set Backs for CAR-T Therapy

Late August and early September was a period of big news — both positive and negative — on the CAR-T front. On the positive side, Novartis’ received the first FDA approval of a CAR-T therapy for Kymriah (tisagenlecleucel), for the treatment of children and young adults with B-cell precursor acute lymphoblastic leukemia that is refractory or in its second or later relapse.  The new treatment was approved based on Phase 2 results that saw a 63% complete response rate and 19% complete response with an incomplete hematologic recovery, as well as relapse-free survival at one year of 60%. Using standard therapy, the historic one-year survival rates have been considerably lower — 20% in children and only 5-10% in adults. As has been true of all CAR-T therapies to date, the major adverse events were the severe ones associated with cytokine release syndrome. Additionally, the treatment, when successful, eliminates the patient’s B-cells and thus, their ability to make antibodies; as a result, surviving patients require monthly intravenous infusions of immunoglobulins to support their immune system.


The second big positive news announcement was the agreement by Gilead to buy Kite Pharmaceuticals for $11.9 billion. Kite’s CAR-T candidate, axi-cel, is expected to receive FDA approval in late November as a new treatment for adult patients with relapsed, aggressive forms of non-Hodgkin’s lymphoma who are not eligible for bone marrow transplant. (Novartis is expected to file for approval in lymphoma by year end as well.)


Both Kymriah and axi-cel are autologous CAR-T therapies with complex manufacturing requirements. In each case, T-cells are extracted from patients, shipped to cell processing plants for genetic programming to fight the patient’s cancer, and then shipped back to the medical center for reinfusion into the patient. The complex procedure takes substantial time — 22 days for the Novartis therapy and about 17 days for Kite’s — and is responsible in part for the high cost of therapy.


As a result, a number of efforts are underway to develop “off-the-shelf” allogeneic CAR-T therapies. Unfortunately, the most advanced of these — UCART123 from France’s Cellectis — received a significant setback in early September, when FDA placed a clinical hold on the company’s two Phase 1 trials. In one of those studies, focused on acute myeloid leukemia, the first patient treated died following an incidence of cytokine release syndrome that worsened and became fatal. In the other study, focused on blastic plamacytoid dendritic cell neoplasm, the first patient also developed cytokine release syndrome, but her condition resolved after treatment. Cellectis is now working with clinical investigators and FDA to restart the studies with amended protocols and lower doses of UCART123. The company is also partnered with Pfizer and Servier on a second CAR-T treatment, UCART19.


Cytokine release syndrome is a known risk of CAR-T therapies, and the Cellectis studies employed the same pre-conditioning regimen of fludarabine and cyclophosphamide that was used in the Juno autologous CAR-T trials that were halted and discontinued as a result of multiple patient deaths. As a result, it is unknown whether allogeneic CAR-T approaches may present unique risks; fears of possible problems with graft-versus-host disease have been considered but not as yet seen in trials to date. In any case, there are a number of other groups pursuing allogeneic CAR-T treatments including Novartis/Kite, Adicet Bio/Regeneron, and Fate Therapeutics/Memorial Sloan Kettering.


A big question for the ultimate success of allogeneic CAR-T approaches is their differentiation versus autologous treatments. While autologous CAR-T treatments at present require a complex, time-consuming manufacturing process, the developers of these therapies are racing to minimize manufacturing turn-around times and costs. Moreover, manufacturing advances are emerging from development at companies like Medcision, GE Healthcare’s cell therapy division, and Germany’s MiHenyi Biotec that would enable hospitals and researchers to manufacture CAR-T treatments on site themselves. If cost and time differences between allogeneic and autologous CAR-T therapies are significantly reduced, and the potential risk of GvHD becomes a real concern, the potential competitive advantage of an allogeneic approach might become less clear-cut… perhaps honing in on benefits such as the greater reliability of having a sufficient cell batch to treat the patient.