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CAR-T Combination with Immunomodulatory Agents: Oncolytic Viral Therapy

المؤلف:  Armin Ghobadi & John F. DiPersio

المصدر:  Gene and Cellular Immunotherapy for Cancer

الجزء والصفحة:  p77-78

2026-09-08

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Oncolytic viruses (OV) have emerged as encouraging agents for the treatment of solid tumors. They are currently being engineered to specifically target cancer cells, which they infect, undergo replication, and induce lysis. OVs are also used as a vehicle to carry genes encoding cytokines, chemokines, enzymes, or antibodies to further bolster their therapeutic potential. The recent approval of talimogene laheparepvec (T-VEC), human herpes simplex virus carrying recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) for the treatment of melanoma, has increased the interest in the field and resulted in a boom of clinical trials assessing the use of OV therapy in a myriad of tumors. OV therapy is able to release tumor antigens that were previously hidden from the immune system, promote a strong anti-tumor response, and debulk solid tumors. This provided a strong rationale to combine OVs with CAR-T cell therapy, and several strategies have been employed. One study aimed to use OV as an approach to overcome the failure of T cells to migrate to the highly immunosuppressive tumor milieu of neuroblastoma. The oncolytic adenovirus Ad5d24 was engineered to express IL-15 and RANTES, which are known in inducing T cell migration and survival. When combined with CAR-T cells directed against the tumor antigen GD2, the apoptosis of cancer cells was accelerated and the intratumoral concentration of CAR-T cells was increased. This led to an increase in the survival of tumor-bearing mice. Further studies assessed the possibility of blocking inhibitory immune checkpoints such as PD-L1 by local production of anti-PD-L1 mini-antibodies to improve CAR-T efficacy. The co-administration of the OV expressing PD-L1-blocking mini-antibody, CAd- VECPDL1, with CAR-T cells directed against HER2 in a prostate cancer xenograft mouse model led enhanced antitumor activity compared to the administration of each element as a monotherapy. This strategy was further optimized by allowing the OV to co-express the PD-L1 mini-antibody and IL-12p70 to prevent the loss of CAR-T cells from the tumor site in a head and neck squamous cell carcinoma xenograft mouse model. This proved to be superior to Cad-VECPDL1, with substantial improvement in overall survival. Surprisingly, this result was not reproduced by coadministration of CAR-T cells and systemic infusion of anti-PD L1 antibody. A different approach engineered OV to express the same tumor antigens targeted by the CAR-T cells as a strategy to re-stimulate the CAR-T cells and enhance their functions. These promising strategies opened the door to a myriad of other opportunities that can be exploited by combining OVs which act as a local source of multiple proteins to enhance CAR-T effectiveness. In addition to delivering immunostimulatory cytokines and ICIs, we can envision other tactics such as using OVs to deliver immune co-stimulatory molecules, molecules targeting immunosuppressive cells or metabolic pathways, pro-apoptotic molecules, or molecules that are able to alter the structure of the tumor microenvironment such matrix metalloproteinases.