אימונולוגיה של גידולים ואימנו-אונקולוגיה

MYC Reprogramming as a Bedside Immunotherapy for Solid Tumors

This project aims to develop a novel therapeutic approach for patients with solid tumors who have failed standard treatments and have limited therapeutic options.

Tat-MYC is a fusion protein that integrates the protein transduction domain of HIV-1 Tat with the human MYC protein (c-MYC). The incorporation of the HIV-1 Tat transduction domain enables MYC to efficiently penetrate cells without energy expenditure or receptor engagement. Transient elevation of intracellular MYC protein levels has been shown to resensitize exhausted circulating anti-tumor T cells and may facilitate the reactivation of tumoricidal T-cell function. A previous phase I dose-escalation study conducted at the Davidoff Cancer Center demonstrated activity in the highest dose cohort using a cell-therapy-based drug incubation approach. Building on these findings, our team is developing a bedside drug-delivery strategy using an experimental delivery system, with the goal of implementing this treatment directly into clinical practice if successful.

Immunological Effects of Ketogenic Diet in Advanced Cancer

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of metastatic cancer, especially in melanoma, Cutaneous Squamous Cell Carcinoma (cSCC), and Renal Cell Carcinoma (RCC). However, response rates remain below 50%, highlighting the need for novel strategies to enhance therapeutic efficacy. The ketogenic diet (KD), a high-fat, low-carbohydrate regimen that induces metabolic shifts towards fat and ketone utilization, has shown potential in modulating immune responses.

Our lab previously discovered that melanoma tumors responding to immunotherapy exhibited enriched mitochondrial metabolism, linked to energy production from fatty acids and ketones. Preclinical studies indicate that KD may enhance tumor immunogenicity and augment ICIs’ effectiveness, particularly in melanoma and renal cell carcinoma (RCC) mouse models.

Our pilot study conducted in melanoma patients demonstrated KD’s feasibility and tolerability, alongside a significant elevation in serum interleukin-2 (IL-2), a cytokine associated with enhanced anti-tumor immunity. Building on these findings, we propose a prospective, controlled, sequential two-arm clinical trial to evaluate KD’s impact on immunological parameters, metabolic changes, and clinical outcomes in patients receiving immunotherapy for melanoma, cSCC, or RCC. The study will assess immune cell function, cytokine profiles, microbiome alterations, and metabolic markers, employing advanced analytical techniques (CyTOF, RNA sequencing). This research may provide critical insights into the interplay between diet and cancer immunotherapy, potentially paving the way for integrative dietary interventions as adjuncts to existing treatment protocols.

Expanding the Clinical Impact of Tumor-Infiltrating Lymphocyte Therapy

Tumor-Infiltrating Lymphocyte (TIL) therapy is a pioneering form of adoptive cell transfer (ACT) that harnesses the patient’s own immune system to target solid tumors. Unlike chimeric antigen receptor (CAR) T-cell therapy, which relies on genetic engineering to target surface proteins, TIL therapy capitalizes on a naturally occurring population of T cells that have already successfully migrated into the tumor microenvironment. These cells possess a distinct advantage: they are polyclonal, recognizing a broad repertoire of tumor-specific antigens, including unique neoantigens arising from tumor-specific mutations.

While TIL therapy has demonstrated historic success in metastatic melanoma, our laboratory is focused on optimizing manufacturing and treatment protocols to overcome current limitations and extend its efficacy to other difficult-to-treat solid tumors. Successful optimization of this approach will enable rapid integration of TIL therapy into clinical use.