Lecture on Cancer Immunotherapy and Targeted Therapy

Introduction to Immunotherapy

• Interest in cancer immunotherapy, particularly in the tumor microenvironment.
• Historical reference to interferon activity against neuroendocrine tumors.
• Dr. Kulkey introduces Dr. Minor Kim from Columbia to discuss vascular regulation in liver metastases of pancreatic neuroendocrine tumors (Nets).

Vascular Regulation in Liver Metastases

• Pancreatic neuroendocrine tumors often develop liver metastasis (40% of patients at diagnosis).
• These tumors are immunosuppressive, limiting efficacy of current immunotherapies.
• Urgent need for new therapeutic targets to control liver metastasis in pancreatic neuroendocrine tumors.
• Focus on angiogenesis and angiopoietin 2 (Ang2) as a target.
  • Ang2 is upregulated in human pancreatic neuroendocrine tumors with liver metastasis.
  • High levels of Ang2 correlate with poor survival.

Mechanism of Angiopoietin 2

• Ang2 destabilizes blood vessels, contributing to vascular leakage and impaired immune cell infiltration.
• Targeting Ang2 can reduce vascular leakage and improve endothelial integrity.

Experimental Studies on Ang2

• Use of mouse models to study Ang2.
• Blocking Ang2 reduces liver metastatic burden and improves mouse survival.
• Ang2 blockade increases T cell infiltration into liver metastases.
• Combined treatments with Ang2 and immune checkpoint inhibitors.

Tumor Infiltrating Lymphocytes (TILs) in Neuroendocrine Tumors

• Use of TILs for anti-tumor immune response in various cancers.
• TILs can be expanded from pancreatic neuroendocrine tumors.
• TIL cultures show high expression of CD4 positive T cells and certain immune checkpoints.
• Potential for targeting TILs with checkpoint inhibitors like TIGIT and CD39.

CAR T Cell Therapy for Neuroendocrine Tumors

• Development of CD17 CAR T cells targeting neuroendocrine tumors.
• Third generation CAR T cells show enhanced anti-tumor activity compared to second generation CAR T cells.
• Activation of multiple T cell signaling pathways with third generation CAR T cells.

CDK 4/6 and MEK Inhibition in Pancreatic Neuroendocrine Tumors

• CDK 4/6 and MEK pathways are dysregulated in pancreatic neuroendocrine tumors.
• Combination therapy shows synergistic activity against tumor cells.
• In vivo studies demonstrate prolonged tumor suppression with combination therapy.
• Potential for combination therapy to sensitize tumors to immune checkpoint inhibitors.

B7x Signaling Pathway in Neuroendocrine Tumors

• B7x, a checkpoint protein, is overexpressed in pancreatic neuroendocrine tumors.
• Correlation with tumor size and stage.
• Antibody targeting of B7x suppresses tumor growth and enhances T cell infiltration.
• Potential for targeting B7x as a therapeutic strategy.

Discussion

• Future directions include understanding immune microenvironment changes over time.
• Importance of further experimentation and clinical trials for novel treatments.
• Consideration of preclinical models and challenges in translating therapies to clinical settings.