Optimizing Active Immunotherapy of Melanoma Through Metabolic Reprogramming of Melanoma Antigen-Specific CD8+ T Cells Combined with Checkpoint Blockade
Abstract
FY18 PRCRP Topic: “Immunotherapy” and “Melanoma and other skin cancers;” FY18 PRCRP Military Relevance Focus: Cancer treatment that may impact mission readiness and the health and well-being of military members, Veterans and their beneficiaries, and the general public. The scientific objective and rationale for the proposed project are to improve treatment of metastatic melanoma, a potentially deadly form of skin cancer. The immune system can be trained to eliminate cancer cells, but cancers have developed mechanisms to fight back. Active immunotherapy, which aims to use the immune system to treat melanoma, is already having successes in a few, but not the majority, of patients. Active immunotherapy can use vaccines to induce an immune response against melanoma; it can isolate lymphocytes from a patient’s tumor, grow them up in tissue culture, and then transfuse them back into the patient; or it can use reagents in form of so-called checkpoint blockers that increase the ability of lymphocytes to kill tumor cells. Alas, once lymphocytes that could potentially kill cancer cells reach the tumor, they often lose their functions and die. This is in part due to the lack of sugars (a key nutrient for lymphocytes) within tumors. Without sugars, lymphocytes have to switch to other nutrients, such as fats, to gain energy in order to survive. Many lymphocytes are apparently not able to make this dietary change and therefore starve within the tumors. It is possible to change the dietary choice of lymphocytes before they enter tumors by using a drug, a so-called PPAR a agonist that is already approved for use in patients with high cholesterol. This drug instructs cells to use fats rather than sugars, and we have shown in mice that this drug increases the effectiveness of active immunotherapy of melanoma. Our objective for the experiments described in this application is to develop a treatment regimen with the PPAR a agonist drug that is suitable for use in humans and to ensure, using human clinical melanoma samples, that the treatment improves the fitness of human melanoma-specific lymphocytes. (a) Near-term impact and ultimate applicability: Before the drug that changes the lymphocytes’ diet can be used with immunotherapy in melanoma patients, additional pre-clinical experiments are needed. Then the treatment would have to be tested in clinical trials. The clinical trials would be designed to show safety of the drug combined with other immunotherapies. Follow-up trials would assess efficacy of the combination treatment. If the clinical trials show that treatment is safe and improves the outcome of active immunotherapy individuals with late stage melanoma would be eligible for this treatment. (b) It would help patients with late stage melanoma who receive active immunotherapy, either in form of checkpoint blockade, a treatment that already is approved for melanoma therapy, or a melanoma-specific vaccine or transfer of expanded melanoma-specific T cells derived from the patient’s tumor; the latter two approaches are at this stage experimental and not yet licensed for melanoma treatment. (c) The clinical application is to add the PPAR a agonist drug to other active immunotherapies such as checkpoint blockade, vaccination, or lymphocyte transfer. If, as expected, the drug increases the effectiveness of active immunotherapies, the benefit would be that it would prolong the patient’s life and potentially increase the rates of cures. The risks associated with the PPAR a agonist drug are minimal; it has been used without serious side effects in thousands of individuals to treat their high cholesterol. Potential risks would relate to the active immunotherapies; both checkpoint blockade and transfer of in tissue culture expanded lymphocytes are associated with significant adverse events. (d) Projected time to achieve a patient-related outcome? If the grant would be funded, we would know within a 3-year period if it would be wort
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910485
Entities
People
- Hildegund Ertl
Organizations
- United States Army
- Wistar Institute