Immunotherapy has been remarkably successful in the treatment of melanoma, but not all patients benefit from therapy and its effects is in most cases temporary, followed by development of resistance. Immunotherapy largely relies on active and persistent T cells, and thus elucidating regulatory mechanisms of T cell function is of paramount importance to the development of more effective immune therapies. CDK4 and CDK6 are closely related kinases that are known to control cell cycle progression.  Recent studies reported that CDK4/6 inhibitors unexpectedly stimulate T cells and tumor immunity, but the underlying mechanisms remain incompletely understood. Efforts to translate these findings to the clinic have been disappointing thus far, with the combination of CDK4/6 inhibitors with immune checkpoint blockade showing modest efficacy and increased toxicities in clinical trials. Since CDK4/6 inhibitors both activate certain function of T cells, but they also block their proliferation, the path to clinically exploit the immunostimulatory properties of these drugs remains unclear. The overall objective of this application is to elucidate mechanisms underlying the immunostimulatory properties of CDK4/6 inhibitors, and to leverage those properties to potentiate melanoma immunotherapy.

Brain metastases remain a leading cause of death in patients with metastatic melanoma. One of the most exciting advances in the treatment of CNS metastases was combined checkpoint inhibitors reporting high response rates. Unfortunately, not all respond. Additional pathways to utilize immune mechanisms to clear CNS metastases are needed. Natural killer cells (NK cells) are the first line of defense against tumors since they can work without the need of additional cells or chemical signals. We have developed a novel method to collect NK from donors, grow them to large numbers in a controlled setting to create a cell bank available for multiple treatments, “off the shelf” NK cells. These cells have shown anti-tumor effects throughout the body in addition to penetrating the blood brain barrier and exerting an anti-tumor effect in a pediatric leukemia patient. We have developed a technique used when expanding the universal donor NK cells that confers relative TGFß resistance (UD TGFßi NK cells). Our study,  the first study of its kind to use UD TGFßi NK cells against brain metastases, will recruit patients with metastatic melanoma with brain metastases. We will generate preliminary scientific data on how the cells travel in the body, survive, enter the brain, attack malignant cells, and interact with the patient’s immune system. We will also assess the preliminary efficacy of this treatment against melanoma brain metastases patients.

Current immunotherapies have dramatically improved clinical outcomes, but more than half of metastatic melanoma patients have poor responses and primary resistance. With time, many cancer patients develop acquired resistance and tumor progression. Nearly one third of patients with metastatic melanoma who initially respond, eventually develop drug resistance and tumor progression within 3 years. To improve overall clinical outcomes and patient survival, new immunotherapeutic strategies are urgently needed. Initial studies in our lab suggest that blocking mitochondrial (powerhouse of the cancer cell) activity generates melanoma rejection killing cancer cells. Through our work, we hope to provide potential new immunotherapies that take advantage of targeting natural killer cells and the possibility to engineer these cells for melanoma treatment.

The translation initiation complex (or TIC) is one of the last unexplored targets in cancer therapy or melanoma. Protein production is tightly controlled by a complex of four main proteins, which are overexpressed in cancer (including melanoma). As a result, tumor-causing genes are produced more abundantly, promoting cancer and melanoma. Over the past decade, we have been able to characterize small molecule inhibitors that interact with components of this machinery, interfere with its assembly, and yet – cause minimal effects on melanocytes or non-transformed cells, while killing melanoma cells more effectively than other tumors. We propose to select the most effective small molecule inhibitors of this machinery to enable an understanding of how they work and to demonstrate their effectiveness in preclinical models.