Engineering Multimodal Immunotherapies against Small-Cell Neuroendocrine Tumors

Endeavor Award (2023-Present)

Stanford University: Julien Sage, PhD; K. Christopher Garcia, PhD; Crystal Mackall, MD; Rogelio Hernández-López, PhD

Julien Sage, PhD

K. Christopher Garcia, PhD

Crystal Mackall, MD

Rogelio Hernández-López, PhD

Small-cell neuroendocrine tumors (SCNTs) represent an aggressive group of difficult-to-treat tumors with shared characteristics that pose significant challenges in patient care. SCNTs include small cell lung cancer, Merkel cell carcinoma, and other aggressive malignancies arising in diverse tissues, such as the breast, prostate, pancreas, and bladder. In addition to SCNTs that are diagnosed as primary tumors, SCNTs may arise from other existing tumors that become resistant to therapy. Unfortunately, the number of SCNT-related deaths is increasing, necessitating urgent breakthroughs in treatment strategies. Current options, such as chemoradiation therapy, show limited effectiveness due to rapid tumor resistance, and immunotherapy in these tumor types has met with limited success. However, the shared common histological features and molecular programs of SCNTs indicate that there are opportunities to harness the potential for targeted therapies tailored to their unique traits. This Endeavor project aims to overcome the challenges associated with SCNT treatment by focusing on immunotherapies and developing a deeper understanding of the genetic drivers of these tumors.

This project will harness cutting-edge immunotherapeutic approaches to develop novel therapies that activate the immune system against SCNTs. The team plans to reprogram the tumor microenvironment using engineered cytokines to activate the innate and adaptive immune system, especially T cells, to target SCNTs effectively. They will also combine CD47 blockade with chemotherapy to stimulate antitumor macrophages’ phagocytic activity against SCNTs, and use antibodies against tumor-specific surface markers to enhance the therapy’s specificity and efficacy. Finally, the team will engineer and optimize CAR T cells to combat SCNTs with superior potency and reduced toxicity compared to existing CAR T cell approaches. The project will use a highly collaborative approach and bring experts together from different disciplines, including structural biology, immunology, and cancer biology, to tackle the complex challenges presented by SCNTs comprehensively.

Successful implementation of these novel therapies could significantly extend overall survival rates and improve the quality of life for patients suffering from these aggressive tumors. By reprogramming the tumor microenvironment, enhancing the activity of myeloid cells, and engineering T cells with synthetic receptors, this project aims to unleash the full potential of the immune system against SCNTs. Moreover, these discoveries and therapies could also be applicable to other cancer types, given the common molecular features observed across SCNTs. By targeting specific vulnerabilities in the tumors and leveraging the power of the immune system, the project has the potential to open new avenues for precision oncology and more personalized cancer treatments.