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The 2022 Tandem Meetings | Dendritic cell/tumor fusion vaccine in transplant and CAR-T recipients
Poorva Bindal, MD, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, explains the rationale for using a dendritic cell/tumor cell fusion vaccine to prevent relapse following allogeneic hematopoietic stem cell transplantation (alloHSCT) or CAR-T therapy. Previous experiments have shown improved outcomes for patients treated with a fusion vaccine. A strategy combining CAR-Ts with the fusion vaccine to induce a potent immune response and activate CAR-Ts is currently being explored. Moving forward, Dr Bindal gives an overview of a Phase I clinical trial evaluating this fusion vaccine in patients with acute myeloid leukemia (AML) who have received alloHSCT (NCT03679650). The study found that patients with lower TGF-β levels had a better response to the vaccine, which led to pre-clinical experiments examinating the impact of a TGF-β inhibitor in combination with the fusion vaccine. In vitro and in vivo are showing enhanced cytotoxicity and decreased levels of immunosuppressive T-cell subsets. This interview took place at the Transplantation & Cellular Therapy (TCT) Meetings of ASTCT™ and CIBMTR® 2022 in Salt Lake City, Utah.
Transcript (edited for clarity)
This is work that my mentors, Dr Avigan, and Rosenblatt have been leading for several years. So at our institution, we have developed a vaccination in the hybridoma format where we fuse dendritic cells with autologous dendritic cells with tumor cells from the patients. And the idea really is that the fusion cell would present a broad area of antigens from the tumor cell to the T-cells and lead to immunity against the T-cell, against multiple different antigens...
This is work that my mentors, Dr Avigan, and Rosenblatt have been leading for several years. So at our institution, we have developed a vaccination in the hybridoma format where we fuse dendritic cells with autologous dendritic cells with tumor cells from the patients. And the idea really is that the fusion cell would present a broad area of antigens from the tumor cell to the T-cells and lead to immunity against the T-cell, against multiple different antigens. And previously we have had clinical trials led by Dr Rosenblatt at our institution, where we have shown that the survival was significantly better in patients who got the fusion vaccine after they had attained a post-chemotherapy remission. Building on that, so for CAR-T therapy, also, we are now working on a combinatorial strategy with the fusion vaccine and CAR-T with the idea that the vaccine would induce an immune response in the innate T-cell, in the resident T-cell population, and also activate the CAR-Ts through the native TCR to increase persistence hopefully even despite the loss of the single antigen target of that CAR cell. So we have great preclinical data from that work from our Avigan lab. And we are starting to bring this to the clinic in the form of a phase one trial.
In that clinical trial that I was mentioning earlier with Dr Rosenblatt tested the dendritic cell and the tumor fusion vaccine in patients with AML who had attained a remission post-chemotherapy. We actually performed, or my colleagues and [inaudible] from our group actually performed the transcriptome analysis, comparing the transcriptome profile of responders versus non-responders. And in that we saw that a lower level of TGF beta was associated with a better response to the vaccine. So from that came the hypothesis that maybe inhibiting TGF beta in these populations may lead to a better response.
So we are currently working with a preclinical murine model where we are using TGF beta inhibition in combination with the vaccine to see if there is a benefit. So far, we have been able to demonstrate in our in vitro experiments that there is enhanced cytotoxicity with that combination. And it does seem to be acting on the immunosuppressive T-cell subsets. we saw a decrease in the expression of PD-1 and FOXP3, and in our in vivo experiments, we have seen some survival benefit in the mice that were treated with the combination.