Project Grant K08CA283285

LOCAL NANO-IMMUNE MODULATION FOR THE SYSTEMIC TREATMENT OF LYMPHOMA - PROJECT SUMMARY THE BROAD OBJECTIVES OF THIS K08 PROPOSAL ARE (1) TO FACILITATE THE DEVELOPMENT OF NECESSARY SKILLS THAT WILL ALLOW THE PI, DR. ADAM LIN, TO ACHIEVE HIS LONG-TERM GOAL OF BECOMING A SUCCESSFUL PHYSICIAN-SCIENTIST FOCUSING ON BRIDGING IMMUNE-BASED NANOTECHNOLOGY FOR THE TREATMENT OF LYMPHOMA AND OTHER HEMATOLOGIC MALIGNANCIES, AND (2) TO INVESTIGATE THE ANTI-LYMPHOMA IMMUNE MECHANISMS AND PATHWAYS CAUSED BY THE PHOTOTHERMAL THERAPY PLATFORM. THIS PROPOSAL CONCERNS EVALUATING A NEW THERAPY PLATFORM DESIGNED FOR RELAPSED/REFRACTORY B CELL LYMPHOMAS, WHICH ARE CLINICALLY CHALLENGING TO TREAT ESPECIALLY RELAPSING AFTER AUTOLOGOUS STEM CELL TRANSPLANT OR CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY. IMMUNOTHERAPIES SUCH AS IMMUNE CHECKPOINT INHIBITORS OR BISPECIFIC ANTIBODIES HAVE LIMITED EFFICACY DUE TO THE SUPPRESSIVE TUMOR MICROENVIRONMENT AND SYSTEMIC IMMUNE SUPPRESSIVE CONDITIONS. THEREFORE, METHODS THAT ALTER LOCAL AND SYSTEMIC IMMUNE MICROENVIRONMENTS ARE NEEDED TO IMPROVE THE RESPONSE TO IMMUNOTHERAPIES. RADIATION THERAPY (RT) HAS BEEN DESCRIBED AS ALTERING THE IMMUNE MICROENVIRONMENTS IN LYMPHOMA THAT GENERATE A SYSTEMIC IMMUNE RESPONSE. HOWEVER, THIS PHENOMENON HAS NOT BEEN OBSERVED CLINICALLY. CONVERSELY, PHOTOTHERMAL THERAPY (PTT) GENERATES A STRONG T-CELL RESPONSE IN SOLID MALIGNANCY MODELS BY PROMOTING A PRO-INFLAMMATORY T-CELL LANDSCAPE. PTT IS CREATED BY IRRADIATING SPECIALLY DESIGNED GOLD NANOPARTICLES WITH NEAR-INFRARED LIGHT. THE NANOPARTICLES ABSORB THE LIGHT AND TRANSFER THE ENERGY INTO HEAT, LEADING TO VERY LOCALIZED ABLATIONS. WE DESIGNED A PTT PLATFORM USING BRANCHED GOLD NANOPARTICLES TO CARRY TOLL-LIKE RECEPTOR 9 AGONISTS, CPGS, AS AN IMMUNE STIMULANT AND FOUND THAT PTT WITH CPGS INCREASED AN ANTI-LYMPHOMA SYSTEMIC RESPONSE, INCLUDING INCREASES IN MEMORY T CELLS. THEREFORE, WE HYPOTHESIZE THAT OUR PTT/CPG PLATFORM CAN CREATE A STRONG ANTI-LYMPHOMA T CELL RESPONSE THAT CAN SYNERGIZE WITH IMMUNE-BASED TREATMENTS. TO TEST THIS HYPOTHESIS, WE PROPOSE THE FOLLOWING SPECIFIC AIMS: (1) CHARACTERIZE THE ANTI-LYMPHOMA IMMUNE MECHANISM OF PTT/CPG IN B CELL LYMPHOMA MODELS, (2) DETERMINE THE SYNERGISTIC ANTI-LYMPHOMA EFFECTS OF PTT/CPG COMBINED WITH T CELL ENHANCING IMMUNE-BASED TREATMENTS IN LYMPHOMA MODELS, AND (3) DETERMINE THE ANTI-LYMPHOMA EFFICACY OF A SUBCUTANEOUS LYMPHOMA LYSATE/NANOPARTICLE MIXTURE PTT PLATFORM IN LYMPHOMA MODELS. THE CANDIDATE AND HIS MENTORS, DR. KIM AND DR. GORDON HAVE DESIGNED A DETAILED TRAINING PLAN TAILORED TO THE CANDIDATE'S SPECIFIC NEEDS AND GOALS. THE PLAN INCLUDES A RIGOROUS RESEARCH COMPONENT THAT WILL AFFORD THE PI NEW KNOWLEDGE AND RESEARCH SKILLS TO EXAMINE THE PTT/CPG PLATFORM BETTER AND MOVE THIS CONCEPT TO CLINICAL TRIALS. THE SUCCESS OF THIS PROPOSAL WILL PROPEL ADDITIONAL WORK EVALUATING THE COMBINATION OF PTT WITH CELLULAR THERAPIES AND WILL LEAD TO TRANSLATION INTO CLINICAL TRIALS IN LYMPHOMA WITH THE PTT DEVICE. MOST IMPORTANTLY, IT WILL PROVIDE AN EFFECTIVE OPTION FOR OUR PATIENTS WITH RELAPSED/REFRACTORY LYMPHOMAS.