CAR-T therapy: The new sensation in immuno-oncology
Major new approvals of drugs for cancer in the last few years have been in the immuno-oncology field where the body’s own defense system have been empowered to combat cancer. Immune check-point inhibitors like Keytruda, Opdivo, Yervoy and others have been ruling the market with their unique treatment paradigms; Bavencio being the latest one to join the club.
2017 seems to be the year when newer options in immunotherapy based cancer treatment would be available in the form of CAR-T based therapies. CAR-T cells (or chimeric antigen-receptor T cells) are genetically engineered from patient’s immune cells to express artificial receptors on their surfaces, which bind to specific antigens on the surface of cancer cells, directing the body’s own immune system to recognize and attack tumors. Also known as adoptive cell transfer (ACT) therapy, till now this type of treatment is only available to patients registered for clinical trials. Promising results have been shown in these studies in patients with various form of blood-based cancers especially advanced acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Some of the studies, which mostly recruit patients that have not responded to other available treatment options for their form of cancer, showed huge remission rates, of up to 94% in severe forms of cancer.
Quite a few biotech companies are testing their CAR-T based therapies in these clinical trials with Novartis and Kite Pharma leading the race. Novartis has recently received breakthrough status from FDA for CTL019 (tisagenlecleucel), for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The drug already has a breakthrough status for r/r B-cell acute lymphoblastic leukemia (ALL) in pediatric and young adult patients, and was also given a priority review at the end of March. This puts Novartis in a competitive position to enter the market when compared to it’s closest competitor Kite Pharma. Following the breakthrough labels for DLBCL, transformed follicular lymphoma TFL and primary mediastinal B-cell lymphoma PMBCL, Kite Pharma has finished its rolling submission with the FDA for a BLA of axicabtagene ciloleucel (KTE-C19) as a treatment for patients with r/r B-cell non-Hodgkin lymphoma who are ineligible for autologous stem cell transplant this March.
Until recently Juno Therapeutics was also in the race to treat adults with desperate cases of acute lymphocytic leukemia (ALL) with JCAR015 but had to stop the project after 5 deaths due to cerebral edema was reported during the clinical trials. CAR-T based therapies are also associated with other serious side-effects like cytokine release-syndrome, B-cell aplasia and tumor lysis syndrome which occurs mainly as CAR-T cells target both normal and cancerous B-cells. To make the target more specific to tumor cells, protein antigens such as MUC1 and mesothelin are being investigated in numerous other clinical trials. Use of CART-meso, in addition to targeting tumor cells which overexpress mesothelin, would also help in better infiltration of advanced solid tumors like ovarian cancer, epithelial mesothelioma and pancreatic cancer.
Other prominent companies which are also developing treatment options using this technology are Sorrento Therapeutics ( developing CAR.TNK™ Chimeric Antigen Receptor Tumor-attacking NK cells in collaboration with NantKwest), Vor BioPharma (an unit of PureTech Health plc) and BioAtla in collaboration with F1 Oncology. Researchers are also trying to develop off-the-shelf CART-therapy which would involve establishing a bio-bank of CAR modified immune cells from healthy donors and distribute them to required points of care when needed. Cellectis has submitted a first Investigational New Drug (IND) application to the FDA for an off-the-shelf CAR-T candidate, UCART123; phase 1 trials for which would start in patients with acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) if approved. Cell Medica and Fate Therapeutics are some other companies which has teamed up with investigators at Baylor College of Medicine in Texas and the Memorial Sloan Kettering Cancer Center respectively to develop off-the-shelf CAR-T therapies .
All these advancements happening in the field of CAR-T therapy raises a beacon of hope for patients with advanced cancers for whom there are no current available treatments albeit with caution with respect to the known side-effects. With Novartis set to share their recent experimental data at an upcoming medical conference, the research community would be poised to analyse the possible implications of this study both in terms of safety and efficacy. Irrespective of who leads the race and comes up with the first CAR-T based therapy, others would surely benefit from the shared insights and studies.
By Tapashi Mandal
Senior Research Analyst @ Innoplexus