Biopharmaceutical Report II
• Source of anti-CD19 CAR-Ts’ benefit obscure
• Targeting multiple antigens may be necessary, says expert
• Cytokine release syndrome remains a challenge
Chimeric antigen receptor T-cell (CAR-T) therapies for multiple myeloma (MM) drew some cautious expert optimism at the recent meeting of the American Society of Hematology (ASH). However, they also expressed uncertainty about their long-term efficacy, antigen targets and tolerability.
Data from several MM CAR-T studies was presented at the ASH meeting in Orlando, Florida, including clinical data from a National Cancer Institute (NCI) study and preclinical data from Cellectis (EPA:ALCLS), bluebird bio (NASDAQ:BLUE) and academic centers in Germany, Japan and the Netherlands.
Cellectis and bluebird bio did not respond to requests for comment. Novartis (VTX:NOVN), which is also developing its CTL019 for MM but did not present data from its Phase I study (NCT02135406), declined to comment.
Cautious optimism at ASH
CAR-Ts are in very early days, and while they could have a place in myeloma, so far they have not shown as much efficacy as in acute lymphoblastic leukemia, a Massachusetts expert and Dr Yutaka Okuno, associate professor, Department of Hematology, Kumamoto University of Medicine, Japan said. Dr Tomer Mark, associate director, Multiple Myeloma Center, Weill Cornell Medical College, New York, however, expressed optimism about CAR-Ts as potential treatment options for myeloma, saying they could yield long-term remissions.
In Novartis’ Phase I study, a patient with refractory MM received CTL019 after myeloablative therapy with the chemotherapy drug melphalan and autologous stem-cell transplantation, leading to a complete response (CR) with no evidence 12 months after treatment of progression or measurable serum or protein associated with the disease in the urine. The CD19-targeting CART’s efficacy came despite absence of CD19 expression on virtually 100% of the patient’s cells (N Engl J Med 2015; 373:1040-1047).
However, given that patients in the study got stem-cell transplants before CAR-T, it is uncertain whether the efficacy benefit comes from the transplant or the CAR-T, said Dr Rajshekhar
In Novartis’ Phase I study, a patient with refractory MM received CTL019 after myeloablative therapy with the chemotherapy drug melphalan and autologous stem-cell transplantation
Chakraborty, hospitalist, Essentia Health, Brainerd, Minnesota, who is also a research collaborator with the Mayo Clinic in Rochester, Minnesota. Autologous stem-cell transplant is a common treatment used for MM.
A BCMA-targeted CAR-T developed by the NCI resulted in one of six patients treated at the lowest dose level having a transient partial remission (PR), while the other five had stable disease (SD), according to Phase I (NCT02215967) data presented at ASH (abstract no. LBA-1). At higher dose levels, two patients had SD, while one had a very good PR (VGPR). Of the two patients treated at the highest dose, one experienced a stringent complete remission (CR), while the other did not have detectable bone marrow plasma cells four weeks after infusion.
The reasons for CD19-targeting CAR-Ts’ efficacy in myeloma despite the disease not expressing the antigen are unclear, said Okuno and Dr Saad Usmani, director, Plasma Cell Disorders Program, Levine Cancer Institute/ Carolinas Healthcare System, Charlotte, North Carolina. It is possible that myeloma cells pick up some CD19 expression post-transplant, Okuno said. Usmani said it probably has to do with immune modulation and some effects in the bone marrow. Melphalan possibly has some role to play in some of the cytoreduction, but perhaps during immune reconstitution the CAR-T cells are taking immunomodulatory actions where they are causing a much more robust plasma cell cytoreduction, Usmani added.
Many antigens are being explored, Mark noted, and there may need to be different antigens targeted for different patients.
In addition to Novartis’ CD19-targeting CAR-T and the NCI’s anti-BCMA therapy, Cellectis presented preclinical data on a CS1-targeting CAR-T for myeloma (abstract no. 116); researchers from Japan’s Hiroshima University and Miyazaki University presented preclinical data on an anti-CD38 CAR-T (abstract no. 591); and researchers from Würzburg University in Germany presented data on a preclinical CAR-T targeting SLAMF7 (abstract no. 115). bluebird bio’s CAR-T also targets BCMA.
Genmab (CPH:GEN) and Johnson & Johnson’s (NYSE:JNJ) multiple myeloma drug Darzalex (daratumumab) targets, while Bristol-Myers Squibb (NYSE:BMS) and AbbVie’s (NYSE:ABBV) Empliciti (elotuzumab) targets SLAMF7.
A major challenge with CAR-Ts in general is dealing with cytokine release syndrome (CRS), a potentially fatal toxicity, said Usmani. While the current CAR-Ts will suit patients who aren’t too sick, tolerability will make them a challenge for the general myeloma population, he said.
Three patients experienced CRS in the aforementioned NCI study.
While CRS has been an ongoing concern with CAR-Ts, it is likely that such kinks will be worked out as later generations of the therapies appear, said Mark.
Cellectis’ market cap is EUR 910.7m. bluebird bio’s is USD 2.3bn. Novartis’ is CHF 219.8bn (EUR 203.4bn).
Reporter, New York
Alaric DeArment covers cancer drug development for BioPharm Insight. He served as associate editor of Drug Store News from 2008 to 2014, covering branded and generic drugs from development to distribution, retail and specialty pharmacy and regulatory affairs. In 2011-2012, he edited the book Contestation and Adaption: The Politics of National Identity in China. A native of Seattle, he graduated with honors with a bachelor degree in journalism from Ball State University and also lived in China from 2001-2004. Follow Alaric on Twitter @AlaricD_BPI