EHA 2021 | Tumor-intrinsic resistance to immunotherapies in multiple myeloma
Leo Rasche, MD, University of Arkansas for Medical Sciences, Little Rock, AR, talks on single and double HIT events in genes encoding targets for immunotherapy in patients with multiple myeloma. In particular, Dr Rasche talks on biallelic loss of BCMA as a tumor-intrinsic resistance mechanism to BCMA-directed chimeric antigen receptor T-cell (CAR-T) therapy and BCMA-directed bispecific antibody therapy, and talks on the potential use of heterozygous loss as a biomarker. Dr Rasche also comments on the vulnerability of GPRC5D-targeting agents to tumor-intrinsic resistance mechanisms. This interview took place at the virtual European Hematology Association (EHA) Congress 2021.
Transcript (edited for clarity)
As you know, BCMA loss emerges at one of the resistance mechanism to enter in BCMA CAR T-cells. And BCMA loss can be mediated either by a biallelic homozygous deletion of BCMA – BCMA is encoded on chromosome 16p – or by a mutation in combination with a heterozygous deletion. And so, it’s pretty clear that this is a mechanism which can be observed after anti-BCMA CAR T-cells. And at this year EHA, we first described the very same mechanism biallelic BCMA loss after bispecific antibodies therapy...
As you know, BCMA loss emerges at one of the resistance mechanism to enter in BCMA CAR T-cells. And BCMA loss can be mediated either by a biallelic homozygous deletion of BCMA – BCMA is encoded on chromosome 16p – or by a mutation in combination with a heterozygous deletion. And so, it’s pretty clear that this is a mechanism which can be observed after anti-BCMA CAR T-cells. And at this year EHA, we first described the very same mechanism biallelic BCMA loss after bispecific antibodies therapy.
So, this is not terribly surprising; however, it was important to show that this type of resistance mechanism is not only seen after CARs rather than also after bispecific antibody therapy. And if you think about biallelic events, we usually believe that you require two independent hits, like a first hit leading to a heterozygous deletion and then the second hit leading to homozygous deletion, for example. And if you think that way, then a heterozygous deletion can serve as a biomarker.
And what we did is we just looked at our local whole-genome sequencing cohorts. So, we have around 100 patients with whole-genome sequencing data available here at Wurzburg. And we looked not only for BCMA, we looked for all types of antigens or genes encoding for antigens which are currently targeted by bispecific antibodies or CAR T-cells, including GPRC5D, FCRH5, SLAMF7, and so on. And what we found is that all of these other alternative targets to BCMA are also targets of copy number aberrations in multiple myeloma. Again, this is not a huge surprise as we know that copy number alterations are very, very frequent in multiple myeloma. However, it also comes with the concern or the prediction that we will see this type of antigen loss.
Also, in patients treated with alternative bispecific antibodies or CAR T-cells, and most importantly, GPRC5D, an antigen which is currently targeted with different costs and bispecifics and studies are showing, or have already shown, the proof of principle that this target is good to be targeted with immunotherapy showing good response rates. However, here we found a frequency of around 15% of immunotherapy-naïve patients already showing heterozygous deletions, which may indicate some vulnerability at this low cost. And here I’m sort of curious whether we will see GPRC5D loss and other losses in the next couple of years when we move forward with these trials evaluating these antigens in multiple myeloma.
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