ASH 2025 | Intratumoral cellular immunotherapy with autologous SIRPα-low macrophages in NHL: Phase I findings

This year I’m very excited to present the ASH for the first time results from a very novel phase one trial where we utilize autologous macrophages that were manufactured and manipulated to have very low expression of SIRP-alpha and then injected intratumorally for the treatment of patients with relapsed non-Hodgkin lymphoma, including B-cell and T-cell lymphoma. As a background, currently, there’s only one type of cellular therapy approved by the FDA for the treatment of lymphoma, and those are CAR T-cells. CAR T-cells are autologous T-cells, as the name suggests, targeting a very specific antigen called CD19. But the problem that we are increasingly experiencing in B-cell lymphoma in particular is that as we have more and more agents targeting very specific antigens such as CD19, CD20, CD79B, unfortunately relapses particularly for very aggressive B-cell non-Hodgkin lymphoma can be antigen negative. And so none of the currently available FDA-approved options can be of any help for our patients with B-cell lymphoma. In T-cell lymphoma, we also have several targeted agents, and relapses can also be antigen negative. And unfortunately, in T-cell lymphoma, more than in B-cell lymphoma, the bar for approval is very low because very few agents have a potential for a cure. So here comes the clinical rationale for this very novel and innovative cellular therapy where based on very strong preclinical data, macrophages coming from the patient himself or self, so autologous macrophages, were not really manufactured the same way T-cells are manufactured, but they were just exposed to a proprietary cocktail owned by this company called Serpent Immunotherapeutics, and the result was the autologous macrophages became more anti-tumoral, and they down-regulated a receptor called SIRP-alpha, which is typically recognized by macrophages, and tries to give to macrophages a “do not eat me” signal. In this way, macrophages became more anti-tumoral independently from any antigen expressed on lymphoma cells. This was a small phase one trial with a standard 3 plus 3 design. The injections were done intratumorally and in one cohort we just gave the injection in the other we also gave radiation at the same time based on preclinical data demonstrating that radiation may synergize with the intratumoral injection of this modified macrophage. It was a very easy treatment, pretty much treatments, either single agent intratumoral cellular therapy or in combination with radiation, were given every other day for a week, typically on Monday, Wednesday, and Friday. And then patients were observed for limited toxicity for up to 29 days. There was pretty much no grade three or four toxicity. We did not see the typical complication of cellular therapy, such as cytokine release syndrome or immune cell-associated neurotoxicity syndrome. So it is a very safe cellular therapy. But most importantly, patients who were enrolling in this trial by study design had no treatment options left that had been previously exposed to CAR-T or bispecifics. Those are the patients that in our clinic we advise to look into palliative approaches, and those patients in this trial had very significant anti-tumoral activity with significant shrinkage of the tumor not only where the injection was done but also in other locations, some of them experienced a complete remission that seems to be durable in a fraction of them. So now that this phase one trial is completed and the translational work will also be partially presented at ASH and in the near future at Tandem, we’re working toward increasing the dose and the frequency of injections with the hope that by having a higher number of autologous macrophages injected, we may be able to achieve more complete remissions and more durable remissions.

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