Circumventing Pediatric Solid Tumor Microenvironment Resistance by Combinatorial CAR NK and Immunomodulating Therapy
Childhood solid tumors are aggressive cancers in children and adolescents that often reoccur or progress after remission (relapsed) or do not even respond to current treatments (refractory). Over the past 40 years, despite multiple therapeutic approaches, children and adolescents with these relapsed/refractory cancers have a dismal outcome (less than 5% of them will survive 1 year) in large part due to the resistance to therapies induced by the suppressive environment in the tumor. New therapeutic approaches are urgently needed to improve the survival of these patients. Natural killer (NK) cell is a type of immune cell that fights cancer in children and adolescents. Previous studies showed that the more active NK cells found in patients’ tumors, the longer the patients survived. In our previous research in immunotherapy against childhood solid tumors funded by National Cancer Institute, we focused on engineering chimeric antigen receptor (CAR) NK cells to increase the ability of NK cells in specifically targeting cancer cells. Furthermore, we successfully developed a variety of effective therapeutic approaches by combining CAR NK cells with various immune modulators to further improve CAR NK cell anti-tumor activity and better overcome the resistance to NK cells in the suppressive tumor environment. In this application, we plan to identify more effective therapies by rationally combining CAR NK cells with multiple immune modulators that we previously found to be effective, and perform required FDA validations and approval for a clinical trial in children and adolescents with relapsed/refractory solid tumors soon after this grant is concluded.
Our project goals are 1) to improve tumor targeting and cancer cell killing abilities of natural killer (NK) cells by modifying NK cells with chimeric antigen receptor (CAR) against newly identified surface proteins on childhood solid tumors (ROR1, MCAM); 2) to facilitate CAR NK cells penetration into the tumor by further engineering CAR NK cells with a tumor-attracting surface protein (CXCR2); 3) to further improve the killing effect of CAR NK cells against tumor cells by combining a therapeutic anti-tumor antibody called dinutuximab; 4) to make tumor cells better recognized by CAR NK cells by modifying tumor cells with a drug named romidepsin; and 5) to increase CAR NK cell half-life, number and activity by combining a novel agent (anti-CD16-IL15-anti-B7H3 TriKE) that connects tumor cells with NK cells and provides support for NK cell survival and persistence. By combining these therapeutic approaches that we previously tested individually to be effective, we hope to identify more effective CAR NK therapy against solid tumors in children and adolescents. We will next complete the required FDA validations and obtain the necessary approval from the FDA for a future clinical trial to begin at the end of this grant cycle to eventually bring this new therapy into clinic. If successful, our study will identify an optimal combinatorial NK cell based immunotherapy that overcomes the suppressive environment in solid tumors and may ultimately lead to the delivery of a highly effective immunotherapeutic regimen for the treatment of children and adolescents with childhood solid tumors.