Melanoma is a skin cancer that accounts for only 4% of cases but 80% of deaths; in 2014 alone it resulted in approximately 10,000 deaths in the United States. Spontaneous development of anti-tumor immunity is associated with improved clinical outcome, indicating the potential for immunotherapy to increase melanoma patient survival. Anti-tumor immune responses are initiated and regulated within sentinel (tumor-draining) lymph nodes (TDLN), but are often inefficient as the result of local immune suppressive signaling. TDLN-directed tumor immune suppression therefore represents a critical hurdle in effective melanoma immunotherapy. Therefore, there is a significant and unmet need for technologies that increase the delivery of immunomodulatory agents to TDLN-resident immune cells improve the treatment of melanoma. The objective of this R01 project is to develop and validate a sentinel lymph node drug delivery technology to improve immunotherapeutic drug bioactivity within melanoma TDLN. This will be tested in a rigorous preclinical inducible model of BRAF mutated melanoma, which occurs in 50% of human melanomas.
Three aims are proposed:
Aim 1 : Measure specificity of drug accumulation in TDLN versus systemic tissues resulting from LN- versus non-targeted immunotherapy.
Aim 2 : Delineate the immune modulatory effect of LN- versus non-targeted immunotherapy in the BRAFv600E melanoma model.
Aim 3 : Evaluate the therapeutic efficacy of LN- versus non-targeted immunotherapy alone versus in combination with BRAFv600E inhibition on disease progression and animal survival in the BRAFv600E melanoma model. This project is expected to yield several outcomes. First, these studies will define parameters for enhancing the efficacy of melanoma immunotherapy via LN drug targeting. Second, the potential for TDLN-targeted immunotherapy to improve the efficacy of BRAFv600E inhibition in the treatment of advanced melanomas will be established. Therapeutic agents already in human clinical testing or approved for human use will be investigated in this work to ensure the highest potential for rapid clinical translation.
Melanoma is a skin cancer that accounts for only 4% of cases but 80% of deaths; in 2014 alone it is estimated to have resulted in approximately 10,000 deaths in the United States. 5-year survival rates for patients with disseminated disease remain unacceptably low (16%) and melanoma is one of only three cancers whose mortality rate in men is increasing. As a result of its potential to treat disseminated as well as unresectable melanomas, immunotherapy has high potential to improve outcomes in advanced stage melanoma. This work will develop an approach to target immunotherapeutic drugs to sentinel lymph nodes, tissues where adaptive immune responses to tumors are regulated, in order to improve drug bioactivity and immunotherapeutic benefit. This will be accomplished by formulating immunotherapeutic drugs into biocompatible polymer nanoparticles that accumulate specifically in lymph nodes but not systemic tissues at high levels after administration. Whether sentinel lymph node targeting of immunotherapeutic drugs improves therapeutic response will be determined in a rigorous, inducible BRAF mutated mouse model of melanoma. Results of this work will also inform the utility of this immunotherapeutic drug targeting approach to synergize with BRAF inhibitors in the treatment of the ~50% of human melanomas that are BRAF-mutated.
|Francis, David M; Thomas, Susan N (2017) Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy. Adv Drug Deliv Rev 114:33-42|