Invited Lecture(JSH)
Thu. November 2nd   14:00 - 14:30   Room 5: Portopia Hotel South Wing Ohwada A
Invited Lecture13
Genetic and pharmacologic approaches to reprogram the immune microenvironment of liver cancers to enhance immunotherapy
Dan G. Duda
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School
Surgical treatments offer the chance for cures in primary liver cancers. However, many patients experience disease progression after surgery or cannot undergo surgery due to unresectable disease. In such cases, available local and systemic treatment options have had limited efficacy, which led to dismal survival rates. Immunotherapy has emerged as a primary therapeutic modality for advanced cancers. However, most liver cancer patients do not benefit from this treatment alone.

More recent developments have offered renewed hope for using immunotherapy in combination with other treatments for advanced cancers. The rationale for combinations is based on reprogramming the tumor immune microenvironment to enhance immunotherapy responses. Some strategies involve the use of chemotherapy, traditionally the standard of care. Others involve radiotherapy, which has shown feasibility and promise in unresectable settings and is now being tested in a randomized phase III trial NCT03186898. Finally, combinations with antiangiogenic agents are attractive, as these drugs have strongly impacted the management of liver cancer and other advanced malignancies.

Immune checkpoint blockade therapy relies on infiltrating and activating immune effector cells within the tumor microenvironment, and immune responses and vascular function are reciprocally regulated. Structural and functional abnormalities in tumor vasculature are hallmarks of cancer and facilitate immune evasion and treatment resistance. The vascular endothelial growth factor, or VEGF, induces these abnormalities. Posited by Professor Rakesh K. Jain, Harvard University, in 2001, the concept that blocking the VEGF pathway could partially restore vascular function (a process called vascular normalization) was recently validated in clinical studies. Vascular normalization in cancer improves therapeutic responsiveness to other treatments. Significantly, vascular normalization can increase the infiltration of immune effector cells into tumors and convert the immunosuppressive tumor microenvironment to an immunosupportive one. On the other hand, cytotoxics such as radiation or chemotherapy may impact the immune tumor microenvironment as well as immunotherapy efficacy.

Combination strategies are attractive, as they promise durable and profound responses in advanced disease and potentially in earlier stages of cancer. But to achieve this promise more broadly, these concepts require greater understanding based on mechanistic preclinical studies and validation in correlative studies in clinical trials as a basis to establish optimal combinatorial strategies. I will summarize the results from clinical correlative studies and preclinical models of liver cancers.
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