Cyclophosphamide Plus Allogeneic CD4⁺ T Cell Infusion Induces Anti-Lymphoma Immunity Despite Lack of Graft-Versus-Host Disease (GVHD) or Sustained Engraftment.

Recent evidence suggests that tumor-bearing animals contain CD8⁺ T cells that can respond productively to a tumor vaccine, but that these T cells do not respond because of insufficient help from tumor-specific CD4⁺ T cells, which have either been inactivated or turned into anti-tumor suppressor T cells. We therefore devised a strategy to augment anti-tumor immunity by administering cyclophosphamide (Cy), to eliminate suppressor CD4⁺ T cells, followed by combining autologous tumor cell vaccination and infusion of partially MHC-mismatched, or haploidentical, CD4⁺ T cells as a source of T cell help for endogenous CD8⁺ T cells. Interestingly, the combination of Cy followed by haploidentical T cell infusion, with or without vaccine, induced potent systemic anti-tumor immunity resulting in cure of 40-50% of BALB/c mice harboring the A20 B cell leukemia/lymphoma. Depletion of CD8⁺ T cells from the infusate abrogated GVHD but did not compromise anti-tumor immunity. Allogeneic donor spleen cells that contained CD8⁺ T cells engrafted durably and caused lethal GVHD. In contrast, the combination of Cy plus CD8⁺ T cell-depleted spleen cell infusion induced only transient engraftment, peaking on day 7 and declining to undetectable levels by day 14. In the absence of Cy conditioning, allogeneic donor spleen cell infusions did not induce detectable chimerism beyond day 3. In summary, Cy plus allogeneic CD4⁺ T cell infusion induces potent anti-tumor immunity in a mouse model of B cell leukemia/lymphoma. Potential mechanisms of the therapeutic effect include direct tumor cytotoxicity by CD4⁺ T cells or allogeneic CD4⁺ T cell help for endogenous, tumor-specific CD8⁺ T cells.