BMS Marron 2025

Introduction

Dr. Thomas Marron, a significant figure in cancer research, leads the Early Phase Trials Unit at the Tisch Cancer Center, is a Professor of Medicine, Hematology, and Oncology, as well as of Immunology and Immunotherapy at the Icahn School of Medicine at Mount Sinai. In his recent course on Biomedical Science, he addressed the clinical applications of cancer immunotherapy, underscoring the potential of harnessing the immune system to combat cancer.

Immune System Overview

Components of the Immune System

The immune system is composed of various cells, each with specialized functions:

• Phagocytes: These include neutrophils that engulf and eliminate pathogens, initiating immune responses.

• B Cells: Functioning as antibody factories, these cells produce specific antibodies in response to pathogens.

• Cytotoxic T Cells (CD8 cells): These cells are critical for killing virus-infected cells and destroying malignant cells.

• Helper T Cells (CD4 cells): They coordinate the immune response by aiding B cells and cytotoxic T cells.

• Natural Killer Cells: Recognize and kill cells that lack MHC I molecules, acting as a first line of defense against tumors and virally infected cells.

Antigen Presentation

Antigen presentation is vital for T cell activation and involves cooperation between Major Histocompatibility Complex (MHC) molecules and T cell receptors (TCR). MHC class I presents antigens to CD8 cytotoxic T cells, while MHC class II presents to CD4 helper T cells.

Challenges in Cancer Immunotherapy

Why Cancers Escape Immune Surveillance

Cancers can evade the immune system due to mutational landscapes that produce tumor-associated antigens, which might be recognized as foreign or even become tolerant by the immune system. Tumors express certain factors (like PD-L1) that suppress immune responses and recruit cells that further inhibit immune activity.

Mechanisms of Immune Evasion

1. Turning Off Immune Responses: Tumors can express inhibitory molecules that engage checkpoint pathways (i.e., PD-L1 binding to PD-1), effectively silencing T cell responses.

2. Recruitment of Suppressant Cells: Tumors may attract regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs) that inhibit effective immune responses.

Immunotherapy Advances

Checkpoint Inhibitors

Checkpoint blocking antibodies have transformed cancer care by re-activating the immune system against tumors. Notable agents that demonstrate effectiveness include:

• KEYTRUDA (pembrolizumab) and OPDIVO (nivolumab): Both target the PD-1 pathway, fostering T cell reactivity against tumors.

• YERVOY (ipilimumab): Acts as a CTLA-4 blocker, which enhances T cell activation against cancer.

• Combination Therapies: Clinical trials have demonstrated improved survival rates with combinations of checkpoint inhibitors, showcasing their enhanced efficacy.

Patient Studies and Outcomes

Recent studies highlight promising outcomes using checkpoint inhibitors:

• For instance, clinical trials indicate significant survival benefits among melanoma patients when treated with nivolumab, showing a hazard ratio for death of 0.42 (indicating a 58% reduction in the death rate compared to traditional therapies).

Toxicity and Risks of Immunotherapy

Immune-Related Adverse Events (irAEs)

While checkpoint inhibitors are effective, they can precipitate irAEs due to excessive immune activation. These adverse events may include conditions such as:

• Uveitis, pneumonitis, colitis, and autoimmune diabetes.

• Understanding these side effects is crucial for managing patient safety during immunotherapy.

Immune-mediated Toxicity Mechanisms

The immune system may inadvertently target normal tissues alongside tumors, leading to diverse autoimmune symptoms that must be monitored in patients undergoing treatment.

Exploring Future Directions

Neoadjuvant and Combination Strategies

Ongoing trials utilizing neoadjuvant therapies aim to better elucidate immunogenic responses in tumors while exploring biomarkers for predictive responses to immunotherapy. The combination of drugs targeting multiple aspects of the immune system may offer improved outcomes for patients.

Research Initiatives

The Tisch Cancer Institute is also engaged in significant research collaborations, including:

• The CIMAC-CIDC Network: Focusing on enhancing correlative studies in immunotherapy trials to define mechanisms of action, resistance, and optimal patient stratification.

• Innovative Trial Designs: Incorporating strategies to explore the immune microenvironment (TME), understanding how immune responses can be tailored through targeted therapies.

Conclusion

As the field of cancer immunotherapy evolves, the integration of deep immune profiling and innovative trial designs holds promise for improving patient outcomes and increasing the efficacy of treatments. The work of Dr. Marron and his team emphasizes the importance of understanding immune mechanisms in order to enhance therapeutic strategies against cancer.