Cancer vaccines are an elegant concept, but to be clinically beneficial they must be made more practical and more powerful. We have recently completed a clinical trial treating lymphoma patients with a novel and extremely practical vaccination maneuver: intratumoral injection of immunostimulatory """"""""CpG oligodeoxynucleotides"""""""". We have shown that vaccination is well-tolerated and induces partial and complete remissions as well as tumor-specific, CDS T cell immune responses. Pre-clinically, we have described an approach - """"""""immunotransplant"""""""" - that increases the anti-tumor efficacy of vaccination at least ten-fold. Immunotransplant refers to the collection of vaccine-primed CDS T cells followed by lymphodepletion and then T cell re-infusion. This maneuver induces proliferation and activation of the transferred T cells and cures large, established tumors. The transferred T cell proliferation and activation are induced by an increased availability of several """"""""common gamma-chain cytokines"""""""" (e.g. IL- 7, IL-15, IL-21) in the lymphodepleted recipient, though the relative importance of these is not yet known. In the mentored phase of this project we will obtain the pre-clinical data to develop and initiate a rationally- designed immunotransplant trial. We will: (1) Understand the role of the different common gamma-chain cytokines in mediating the pre-clinical anti- cancer effect of immunotransplant, (2) Assess which of 5 standard, lymphodepletive chemotherapy regimens optimally induces the cytokine(s) determined in Aim 1, (3) Determine the most clinically significant immunologic endpoints by correlating clinical and immune response data from our two ongoing intratumoral vaccine trials, and (4) Initiate an immunotransplant trial for patients with low-grade or mantle-cell lymphoma using the intratumoral vaccine described, the conditioning regimen and the immunologic endpoints determined in Aims 2 &3. We hypothesize that, as in the pre-clinical model, immunotransplant will greatly increase the power of vaccination.
By making cancer """"""""vaccines"""""""" more powerful, our project will allow this elegant concept to be of widespread clinical benefit. We have shown that (1) a novel lymphoma vaccine can induce remissions in patients, and that (2) pre-clinically, """"""""immunotransplant"""""""" increases the power of this vaccine at least ten-fold. A clinical trial of immunotransplant will bring this more powerful approach to patients with incurable lymphomas.
| Kohrt, Holbrook E; Houot, Roch; Marabelle, Aurélien et al. (2012) Combination strategies to enhance antitumor ADCC. Immunotherapy 4:511-27 |
