IMW 2021 | CAR-T for myeloma: where are we now and where are we going?

The field of chimeric antigen receptor T-cell therapy is a very exciting and moving field in, moving in the sense that we have a lot going on, and hopefully we will see a lot more over the next few years. As many of you know, ide-cel was approved for the treatment of relapsed/refractory multiple myeloma. It’s a CAR T-cell product which targets BCMA, B-cell maturation antigen. And this is the first CAR T-cell treatment that was approved for the treatment of relapsed myeloma in the States. And so we’re very excited about this.

There are others coming. This first product was Bluebird. It’s managed by Bristol Myers Squibb or BMS. Janssen has a product, cilta-cel. It has a name, and they’ve made a biologics license application to the FDA and there’s supposed to be a readout sometime in the fall. So, hopefully we’ll see a favorable nod from the FDA and that this will also be available. They have, this also targets BCMA, and there are other similar products in the pipeline.

Now, what makes this all kind of interesting is there are other ways of targeting BCMA. One is an antibody-drug conjugate. There’s several that are in clinical trial. There is an antibody BiTE, or a bi-specific T-cell engager, which is something that has an antibody portion on there or something that binds BCMA, and the other part binds usually CD3 on the T-cell. So, it brings the T-cell and the tumor cell in close proximity, allowing the T-cell to kill the tumor cell.

So, these all target BCMA, and again, we’re not sure which will be better. Will we want to use the CAR T-cell? Will the BiTEs suffice or the antibody-drug conjugates suffice or the antibody engagers? Because some are FAB fragments of the monoclonal antibody and some are the whole antibody. So, all remains to be determined.

We also know that there are some targets that are new. GPRC5D is one. That was, had a very interesting readout at meetings earlier this year. Remember specifically the ASCO meeting where talquetamab, the anti-GPRC5D bispecific which binds again, GPRC5D and CD3, again bringing the T-cell close to the myeloma cell, thus allowing it to kill it. It’s very exciting data and good responses. The other thing that’s very interesting is it appears to be independent of BCMA, so even if BCMA is not expressed on the myeloma cell, the bispecific still works.

There are also in clinical trials CAR T-cells directed against GPRC5D, and they appear to be independent of each other. So, if you have a tumor that is no longer responsive to a BCMA CAR-T, it very well may respond to a GPRC5D CAR T-cell treatment.

There are also a variety of other types of CAR T-cells being developed. There are allogeneic CARs, which are very exciting, where a normal T-cell is gene-edited using CRISPR or TALEN technology to knock out the endogenous T-cell receptor, making it no longer alloreactive and then knocking out class 1 expression through a variety of mechanisms. One could be done by knocking out the Beta-2 microglobulin and that decreases class 1 expression. There are things that you could do such as putting in molecules that would allow for the T-cell to become more resistant to checkpoint inhibition and allow it to last longer.

So, these allogeneic CARs are now in clinical trial, where you can essentially identify the patient and determine the eligibility. If they are eligible, they usually receive some form of lymphodepleting chemotherapy, and then the CAR T-cell is infused. So, it gets around the need for having to have the patient’s own T-cells sent to a laboratory for manufacture of the CAR T-cell.

Now, will the allogeneic CAR be better than the autologous? Don’t know. We do know that we still have, at least looking at the data of the approved CAR T-cell, we have a need for improving upon outcomes, because there still are patients who do progress. So, this is sort of CAR-T 101. We’re just starting, and we’re so excited that we’re going to be able to have multiple opportunities to use this type of therapy to treat our patients.