Collaborative and Service Projects

New agents that block immune checkpoints have the potential to revolutionize the treatment of cancers. Anti-CTLA4 and anti-PD-1 antibodies show significant promise in clinical trials. However, the molecular determinants of response are unknown. The mechanism of checkpoint blockade remains one of the most important unanswered questions in oncology. Our preliminary data demonstrate that therapeutic response is determined strongly by tumor genome and homology with foreign antigens present in the microbiome. Here, we seek to define the molecular determinants that define T cell receptor sensitivity for neoantigen and the role of foreign pathogen antigens in stimulating those responses.

Checkpoint blockade immunotherapies are currently some of the most promising strategies for fighting cancer. PD-1/PD-L1 blockade induces measurable responses in 13-26% of patients with many types of cancer by increasing anti-tumor T cell responses 1. In some cases, PD-1/PD-L1 blockade results in rapid and durable anti-tumor responses. Despite the effectiveness of PD-1/PD-L1 blockade, many patients are unresponsive to therapy 2-4. There are two major factors that contribute to poor prognosis: 1) Tumors poorly elicit CD8 T cell responses and 2) if T cell responses are formed, they often fail to infiltrate the tumor or are functionally exhausted 5-7. T cell exhaustion is associated with increased T cell expression of inhibitory receptors such as PD-15.

Certain HIV-infected individuals, known as “elite suppressors,” are able to maintain undetectable viral loads without antiretroviral therapy. In effect, their immune responses to the virus induce a functional cure. Current efforts in HIV research seek to develop vaccines that can achieve this same kind of functional cure in all patients. One promising strategy recently reported in macaques has been to induce an effector memory CD8+ T cell response against SIV by using a Rhesus CMV (RhCMV) vector to deliver SIV proteins. To attempt to bypass the need to infect patients with CMV in order to achieve the effects of the RhCMV-SIV vaccine, we plan to expand non-canonically-restricted CD8+ T cells from the blood of healthy donors using artificial APCs (aAPCs). We will then test whether the HLA-E and Class II-restricted CD8+ Tcells are protective against HIV and if they can kill virally-infected targets.

In this proposal, we wish to demonstrate the feasibility of identifying and expanding neoantigen-specific T cells for adoptive transfer following PD-1 blockade, in order to show that the majority of patients can have melanoma neoantigen-specific T cells expanded from their peripheral blood. We also aim to optimize ex vivo conditions for expansion of functionally and phenotypically optimal T cells for transfer using analysis of T cell function, TCR diversity and affinity to identify optimal neoantigen-specific T cell populations that will allow us to design truly personalized immunotherapeutics in future studies. This is highly clinically significant and represents an outstanding translational project. The work described is quite novel in that for the first time we propose to use peripheral blood cells from patients treated with a PD-1 antibody that we have found are enriched for antigen specific T cells. Our preliminary data suggest that in the tumor and in the periphery, clonality of increased and cells within the tumor can be found in the peripheral blood at low levels. We will expand these infrequent clones with the use of artificial antigen presenting cells, a truly innovative approach to expanding rare T cells within the periphery.

During autoimmune disease, the body incorrectly identifies “self” molecules as foreign and mounts a chronic immune attack. Conventional therapies employ broad immunosuppression, which has provided significant benefits to patients, but can leave these individuals immunocompromised. This limitation, along with the lack of cures for most autoimmune diseases, has sparked intense interest in strategies that could control autoimmunity with vaccine-like specificity, leaving the rest of the immune system intact. Several pre-clinical reports and clinical trials have investigated this theory to combat multiple sclerosis (MS), a neurodegenerative disease in which myelin in the central nervous system (CNS) is attacked by the immune system. An important finding from these studies is that co-administration of myelin peptide and tolerizing immune signals can promote the development of regulatory T cells (TREGS) that ameliorate disease. New knowledge of how signal integration in lymph nodes (LNs) drives tolerance could help address limitations associated with current therapies, such as incomplete control of disease and non-specific suppression.

In multiple myeloma (and many other heme- and non heme malignancies), the bone marrow is enriched for cancer specific T cells. Moreover, the higher efficiency of antigen presentation and greater concentration of central memory T cells in the marrow, make MILs a unique type of cells for adoptive T cells therapy. MILs technology expands and activates these cells ex vivo and then re-infuses them in the patient. In TRD 4 we seek to metabolically reprogram cells to enhance their efficacy and persistence. Collaborating with Dr. Borrello’s group affords us an extraordinary opportunity to test this hypothesis in an ongoing clinical program of Adoptive Cellular Therapy for Cancer. In this regard, our findings are readily translatable. With this collaborative project we hope to not only further Adoptive Cellular Therapy but also develop a tool box for metabolic reprogramming that can be exploited for not only enhancing immunotherapy for cancer but for a vast array of immunologically engineered systems.

This collaboration will enable us to translate our findings regarding immunometabolism to this novel treatment modality for cancer. Aim 1 seeks to exploit the robust molecular biology of CAR T cell generation and T cell genome editing to make these cells more potent effector cells. Aim 2 will define novel media to promote T cell persistence and memory. Aim 3 will harness our small molecule approach to regulating metabolism in order to enhance effector function and promote memory. By developing these three Aims for CAR T cells, we hope to not only further advance adoptive T cell therapy but also develop a tool box for metabolic reprogramming that can be exploited to enhance cancer immunotherapy as well as a vast array of immunologically engineered systems.