DocWire News spoke with Nikhil Munshi, MD, Professor at Harvard Medical School and medical oncologist at the Dana-Farber Cancer Institute, about his recent study which found a mutation leading to the loss of BCMA after CAR T infusion. Dr. Munshi addresses what these findings suggested about BCMA and CAR T resistance, and other therapeutic targets that could address this issue.
This is part two of a three-part conversation with Dr. Munshi. Watch part one, where Dr. Munshi discusses treatment sequencing and selection in multiple myeloma.
DocWire News: Your recent study, published in Nature Communications, found a mutation that led to the loss of B cell maturation antigen (BCMA) after chimeric antigen receptor (CAR) T cell infusion. What do these findings suggest about BCMA CAR T resistance?
Dr. Munshi: So, this is a very important question, which is, why do CART T fail? Almost 80–90%—in some cases over 90%—of patients respond. But for example, [for the CAR T therapy] ide-cel currently the progression free survival (PFS) is nine months. Now, yes, these are very advanced patients. The median line of treatment patients are listed before [initiating treatment] were six, but still, with somebody getting deep responses, why do they relapse? So if we understand that, we can improve the benefit of CART T cells. So in an effort to do that, we have begun to do this, and this particular publication that we had, it was from a very unique patient. It’s a one patient example, but it highlights what could be one of the mechanisms of resistance. This is a patient who got a CART T cell, had a very good partial response (VGPR), more than 90% reduction; [then] after nine months, patient relapsed. And we gave the same CART T to the patient again and did not respond to that.
So why did the patient relapse and why the second CART T cell that work first time did not work second time? So we had eight different samples from this patient before the first CART T, during the CART T, at relapse, and after the second CART T. And we did single cell genomics on this sample, and we did not find significant difference in the immune profile of this patient. Immune cells did not change significantly. However, when we looked more carefully at the myeloma cells, we recognize that the 16th p, the arm of the chromosome, where BCMA is located, was deleted on one side and the second chromosome 16p where BCMA is, there was a mutation which inhibits production of BCMA. So in functional aspect, the patient as the myeloma cells were stopped making BCMA. So loss of the target ended up being a potential cause for drug resistance or CART T cell resistance in this patient. This patient ended up getting the BCMA targeting treatment later on because we didn’t have this data and did not respond. And so that’s what is predictable.
So I think the importance of the studies that loss of BCMA could be one of the potential mechanism. We believe it’s not very common. There are anecdotal cases. As we treat more patients, we’ll look at more data, but it seems to be not the commonest cause, but one of the still possible cause for BCMA loss. It has significance because those patients should not get any of the BCMA or the BCMA targeting treatment. I did BCMA antibody drug conjugate (ADC) blenrep or the bispecific antibodies (BiTEs), so the patient selection would be impacted by this. The other part is that we still need to find out why the majority of the patients relapsed and their response is stopping, so I think that’s the process we are in at the moment—to understand what other immune mechanism leads to patients relapse and or lack of total removal and elimination of myeloma cells from the body.
DW: Apart from BCMA, what are some novel therapeutic targets being researched in MM that are particularly of interest to you?
I think one of the important component for going to the next stage, because until we cure the disease, we got to find improved treatment. And so knowing CART T works very well and the immune system works well … The BiTEs work well too. They’re not yet in the commercial setting yet, but we have very good data from multiple other BiTEs that they do provide significant, similar to CART T, efficacy in many patient populations. So now other targets are being evaluated from the immune point of view. And if you look at what those targets are, they are the ones which are the molecules which are expressed specifically on surface of myeloma cells and are not expressed, or are not functionally important in other cells. The one which has now gone further to having both a BiTE and CART T cell being investigated, is a molecule called GPRC5D, and that’s an exciting second molecule that will provide us good immune targeting.
There’s another one, which is moving forward, is called FCRL5, and another target that is also going forward for some of these mechanisms. So besides this, there are certain other standard myeloma related targets like the CS1 or SLAMF7, which is being investigated. We had investigated NKG2D previously … and then CD38 and CD138 are also targets, although the focus has not yet been CART T or BiTE yet.
So that’s one component of it. The second component to keep in mind to improve the efficacy of CART T, or [similarly], to now change various aspect of the product itself, not just the target, but the product. So it can be that we could have two targets on the CART T cells. We can produce CART T cells with more memory phenotype, like culturing them in protein kinase inhibitor. There are CART Ts which has been gene edited, knock down a PD1 or [similar targets]. There are allogeneic CART T cells so we don’t have to make CART T for each patient. You can take it out of the bottle. And then there are concepts of peptides stimulated T cells being used for vaccination, et cetera. And then we also have other mechanism, for example, if we decrease the shedding of BCMA, then there’ll be BCMA on cells under myeloma cells, using what is called gamma secretase inhibitor, and you can increase efficacy. And then using CART T at an earlier stage of the disease, and quite importantly, using some maintenance treatment so that it can persist and provide better, et cetera, reduction and possibly long-term disease control. And so these are various CART T-related, newer methods being evaluated for immune mechanism.
There are many other targets under investigation for myeloma, not immune driven, but protein degradation using ubiquitin enzyme targeting, or protostome receptors being targeted. There are many genomic and mutation targeting agents such as dabrafenib and trametinib being investigated. So there’s already ongoing studies, but focused on immune function, which is what has been the most successful recently, there are lots of new targets is being evaluated.