Induction of Potent Anti-Tumor Effects by Original and TCR-Redirected CD4 ⁺ Cytotoxic T Cells.

Abstract 1333

Poster Board I-355

The curative Graft versus Tumor (GvT) effect of allogeneic stem cell transplantation and donor lymphocyte infusions is mainly mediated by donor derived T cells recognizing minor Histocompatibility antigens (mHag) presented by malignant cells. Traditionally, CD8+ cytotoxic T cells (CTLs) are considered as “the” effector cells of these anti-tumor responses, whereas a sole helper role is attributed to CD4⁺ T cells. CD4⁺ T cells often possess killer capacities in vitro, raising the possibility that they may also mediate anti-tumor effects without the need for CD8⁺ T cells. Hence, we here explored the feasibility of adoptive immunotherapy with sole CD4⁺ CTLs by testing the therapeutic capacity of a mHag-specific, CD4⁺ CTL (3AB11) in a human GvT model. Rag2^−/−γc^−/− mice were inoculated with BLI detectable, mHag⁺ Multiple myeloma cells. Treatment of established tumors with 3AB11 but not with control CD4⁺ T cells by triple consecutive injections of 30-40×10⁶ cells/day rapidly reduced the medullary growing tumors, illustrating for the first time the feasibility to establish a significant GvT effect by targeting a sole mHag recognized by CD4⁺ CTLs. The therapy was less effective at a higher tumor load and unsuccessful by a single injection of 20×10⁶ cells, underscoring the critical importance of T cell dose-to-tumor load ratio to establish an efficient anti-tumor effect. In further exploration, tumors were also significantly reduced by treatment with “dual antigen-specific” T cells, which were generated by transduction of the T cell receptor (TCR) of clone 3AB11 into recall antigen (Tetanus Toxoid; TT)-specific T cells. Finally, the in vivo persisting dual-specific T cells could be boosted by administration of TT loaded mHag negative B cells, demonstrating for the first time the feasibility and potential advantages of immunotherapy with TCR-transduced “dual antigen-specific” CD4⁺ T cells. We conclude that potent GvT effects may be achieved in clinical trials by targeting a sole mHag antigen with original or TCR-redirected CD4⁺ CTLs.