One of the main reasons for the low efficiency of immunotherapy with immune checkpoint inhibitors in non-inflamed (cold) tumors is the lack of anti-tumoral T cell responses. Arenavirus-based cancer vaccines are ideally suited to induce tumor specific T cells but are hampered by the presence of immunosuppressive factors within the tumor microenvironment. Due to their capacity to promote activation, expansion, and effector function of activated T cells, we hypothesized that 4-1BB agonists could help to overcome intratumoral immune suppression by maintaining or even enhancing the functionality of vector-induced T cell responses.
To test this hypothesis, we initially combined replicating LCMV based vectors (artLCMV) encoding the tumor-associated antigens gp70 or Trp2 with agonistic 4-1BB monoclonal antibody (mAb).
Single administration of vector and 4-1BB mAb prolonged tumor growth control and increased the number of complete responders in the cold B16.F10 tumor model. The combination induced a moderate increase of tumor-infiltrating CD8+ T cells, and positively affected expression of granzyme B, Ki67 and Bcl-XL in tumor-infiltrating antigen-specific T cells. Next, we generated artLCMV vectors co-expressing 4-1BBL together with gp70 or Trp2. In the immunogenic MC38 model, vector-encoded 4-1BBL did not further enhance the already high anti-tumor efficacy of artLCMV-gp70. In the cold B16.F10 model, however, 4-1BBL co-expression increased median survival time and number of complete responders, especially after intratumoral application. This contrasted with systemic application of vector and 4-1BB mAb, as described above. These data indicate that 4-1BB costimulation of T cells is most effective within the tumor, supporting the development of tumor-targeted 4-1BB agonists, which could be applied systemically, as intratumoral injections are not applicable to all cancer patients.
Overall, these experiments confirm the potential of combination therapies with arenavirus vectors and 4-1BB agonists, especially for the treatment of cold tumors, which lack functional T cells.
Hookipa Pharma Inc.
Hookipa Pharma Inc.
J. Strauss, D. Reckendorfer, K. Pojar, T. Pölzlbauer, S. Ahmadi-Erber, S. Schmidt, J. Raguz, J.C. Lampert, K.K. Orlinger, H. Lauterbach: Financial Interests, Personal, Full or part-time Employment: Hookipa Pharma Inc; Financial Interests, Personal, Stocks/Shares: Hookipa Pharma Inc. M. Habbeddine, M. Scheinost: Financial Interests, Personal, Stocks/Shares: Hookipa Pharma Inc.