Abstract 53P
Background
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.
Methods
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).
Results
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.
Conclusions
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.
Legal entity responsible for the study
Hookipa Pharma Inc.
Funding
Hookipa Pharma Inc.
Disclosure
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.