How do CAR T cells compare to conventional therapies, and what are the toxicity concerns of the approach?
Dr Chari: When we think about novel agents that were approved recently based on accelerated strategies such as carfilzomib, daratumumab, selinexor, and belanatamab, they all fall into a single-agent response rate of 20% to 30% and PFS of 3 to 4 months, which can be seen as an unmet need category. Now we have CAR T agents demonstrating 80% to 100% response rates — and bispecific antibodies demonstrating 60% to 80% — in patients often even more heavily pretreated than those initial drugs were. A game changer is the striking efficacy of these T-cell redirection approaches, and that’s what I think is leading them to be considered for earlier use.
The main toxicity is cytokine release syndrome, which typically is amenable to intervention and then after that is pretty well tolerated with manageable hematologic toxicities and minimal nonhematologic toxicities. Neurotoxicity with CAR T was brought up with the CARTITUDE-1 study (ClinicalTrials.gov Identifier: NCT03548207) with 20% all-grade neurotoxicity overall, which was mostly immune effector cell-associated neurotoxicity syndrome (ICANS) and others including issues with movement, neurocognition and neuropalsy. The ICANS resolved and the other neurotoxicities resolved in half of the patients. Closer monitoring and earlier interventions have led to a decrease in these complications. We also have to keep in mind that a lot of these agents are in development, so these toxicity signals may become more manageable as we gain greater experience.
Is BCMA going to remain the priority target for CAR T therapy in MM, or is there also potential in pursuing other targets?
Dr Chari: BCMA is the most advanced target in development and will probably be the first one to get approved. The bluebird bio construct idecabtagene vicleucel has been submitted for approval and is anticipated to be approved sometime this year. The Janssen construct ciltacabtagene autoleucel may be approved later this year, as well. BCMA is first on the scene, but there is interest in other targets. Other targets explored are SLAMF7, GPRC5D, CD38, and CD19. Targets are being investigated as monotherapy, but one question often asked is, “Can we use dual-antigen CAR T agents to try to decrease relapses and increase efficacy?” These studies are also ongoing. Alternative cell types including natural killer (NK) cells and γδ T cells are also under investigation.
For bispecific antibodies, BCMA is the most common target under investigation. Two other targets under investigation were presented at the 2020 ASH Annual Meeting and Exposition: I presented data on G-protein-coupled receptor class 5 member D (GPRC5D) from Janssen2 and Dr Cohen presented data on cevostamab (FcRH5:CD3 T-cell engaging antibody) from Genentech.3 What is really exciting, considering that most historical chemotherapy drugs having a 20% to 30% response rate for 3 to 4 months, is that we are now seeing these bispecific classes all showing impressive responses. These are phase 1 dose-escalation studies, so we should keep in mind that we shouldn’t necessarily be talking about responses, but the fact that some of these cohorts have shown responses between 50% and 80% and many are very durable is really encouraging. Remember, these are phase 1 dose-escalation monotherapy studies in patients who have exhausted all other available therapies! There is also interest in combination strategies, such as the Janssen compounds targeting GPRC (talquetamab) and BCMA (teclistamab) combined with each other, with daratumumab, or with daratumumab and pomalidomide together. Dual antibody therapy strategies are particularly exciting and beg the question, “In the future, can we avoid chemotherapy altogether and use combination immunotherapy strategies like in other hematologic malignancies?”
What will we learn about the use of CAR T for the treatment of MM over the next year? What is necessary to get it established in terms of evidence for a therapeutic option in MM?
Dr Chari: We need to know who the patients are who are eligible and how we make this broader. Up until now, candidates have been primarily younger, fitter patients with nonexplosive disease because of the manufacturing period and the need for bridging chemotherapy. Some of the newer production techniques are trying to reduce the manufacturing period from 4 to 5 weeks to less than 3 weeks. Off-the-shelf strategies involving allogeneic CAR T cells might broaden the number of patients who are eligible as time to CAR T Infusion can be as short as 5 days. In terms of patient selection, there is growing comfort dealing with older patients. Older, fit patients can readily tolerate low-grade cytokine release syndrome, which is manageable with tocilizumab, steroids, anakinra, and additional supportive care agents. Management of infectious complications and hematologic toxicities is also important, whether it be via infection prophylaxis, infection monitoring, or more rarely providing stem cell boosts to patients with pancytopenia.
Putting this all together, optimization of the risk:benefit ratio is the path to getting CAR T more widely established at more than just a handful of academic medical centers.