The long-term goal of Project 4 is to develop an effective, clinically feasible approach to targeting chemoresistant tumor-initiating cells in chronic lymphocytic leukemia (CLL). In the preceding SPORE funding period, we showed that a small subset of circulating or marrow-resident CLL cells within the side population (SP) of tumor cells are drug resistant and have properties associated with cancer initiation. After demonstrating that a tumor vaccine consisting of autologous tumor cells modified to express IL-2 and CD40L could generate a T cell response (vaccine-induced cytotoxic T cells, or VICTs), directed primarily against the SP subset of CLL cells, we now propose to use this information to prepare T cells directed against the SP-associated antigens we previously identified, using ex vivo peptide immunization (Peptide-induced Cytotxic T cells- PICTs). We will also test a strategy for enhancing these T cell responses against the drug resistant and putative tumor initiating SP cells, by genetically modifying the SP-directed T cells to express IL-21, thus rendering them resistant to Treg cell inhibition. We will also administer the modified T cells together with continued """"""""booster"""""""" vaccination with peptides to increase T cell expansion and persistence in vivo. These new strategies will be tested in NSG mice engrafted with CLL cells (Alms 1 and 2).
In Aim 3 we plan to conduct a clinical trial (Aim 3) that will evaluate the most successful approach emerging from the CLL mouse model. The outcome of this project should provide a new and effective means of targeting, chemoresistant CLL-initiating cells, hence complementing extant methods of eradicating bulk populations of non-SP tumor cells. More broadly, it will confimi the existence of clinically relevant subset of CLL progenitors and demonstrate the feasibility of using immunotherapy to target these cells.
An overriding goal of targeted cancer therapy is to eliminate all malignant cells that can initiate the formation of new tumors, rather than simply the obvious general population of tumor cells. The studies outlined here could provide a specific method for eradicating a small drug-resistant group of leukemic stem cells in an otherwise incurable disease.
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