ASH 2024 | PD-1 plus Tim-3 blockade to improve the anti-myeloma activity of T-cells of patients on talquetamab

As you know, we have multiple bispecific antibodies right now for relapsed/refractory multiple myeloma. And unfortunately, there are a group of patients who do not respond at all to bispecifics, and there are patients who initially respond but then relapse. So in our study, we were trying to understand some of the tumor-intrinsic and immune-mediated mechanisms of resistance. So we looked at both compartments in patients who underwent the MonumenTAL-1 trial. So we took patient samples donated by the patients from baseline, cycle 3, day 1, and at time of disease progression. And we looked at the tumor compartment first, and we analyzed by whole exome sequencing, RNA sequencing, and immunohistochemistry to look at GPRC5D expression. 

So from the tumor side, we found that patients eventually at time of relapse develop mutations or losses in GPRC5D, and that was the case for 35% of patients who relapse on talquetamab. And for the rest of the patients, actually, if they don’t lose GPRC5D or are mutated, they actually decrease the expression, and that was shown by the RNA sequencing data. So we saw that for paired samples, patients who had both baseline and time of disease progression, the RNA expression of GPRC5D significantly went down. There’s also GPRC5D RNA expression at baseline that we looked at, and we found that also, even at baseline, if you have higher expression of GPRC5D, that can also be associated with deeper responses as well as prolonged progression-free survival. 

So apart from the tumor, we then looked at the immune microenvironment, and with that, we looked at both peripheral blood and bone marrow. And we looked at also baseline, cycle 3, and time of disease progression. And we used spectral flow to immunophenotype the immune microenvironment, and we did T-cell in vitro functional assays. So our hypothesis was that in the absence of alterations in GPRC5D, we believe that of response or the eventual relapse on talquetamab can be mediated by T-cell dysfunction. And our hypothesis is also that, or our aim was to see if we can reverse it using checkpoint inhibitors. 

So what we did was we immunophenotyped both peripheral blood and bone marrow and we found that the baseline immune microenvironment can predict how well you respond to talquetamab. So if you have more CD3-positive T-cells, if you have more effector memory T-cells, as well as central memory T-cells, and lower terminal cells, that actually predicts better outcomes. 

But also, we noticed that as time goes on throughout treatment, the ability of T-cells to kill myeloma cells decreases. So what we did was we took T-cells from different time points throughout treatment, and we co-cultured them with myeloma cell lines. So we found that as you go through treatment, the ability of T-cells to kill the myeloma cells goes down and that is also probably mediated by T-cell exhaustion, because we looked at the expression of PD-1 and TIM3 over time and we saw that it starts going up and in addition to that we saw that cytokine production was also diminishing also over time which all of which can explain the decrease in efficacy. 

So in order to try and reverse that T-cell exhaustion, we added nivolumab and sabatolimab to block PD-1 and TIM3 respectively and we found that after co-culturing with talquetamab and immune checkpoint inhibitors for 48 hours in vitro, we are able to see that the T-cells’ ability to kill myeloma cells increases by 30 to 40 percent. But all that definitely is still at the research level in the lab, but at least it’s on patient specimens. So the hope is that eventually this will lead to clinical trials where we combine bispecifics, and in this case, talquetamab with immune checkpoint inhibitors, and that could possibly lead to improved outcomes, even in patients who have lower expression, for example, of GPRC5D. And it might even help us in maybe decreasing the dose of bispecific or making it less frequent, which of course, patients would definitely prefer that because it’s less of a burden and less of side effects when you decrease the dose and make it less frequent.

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