Immunotherapy for gastrointestinal malignancies

Abstract

Background: Gastrointestinal (GI) cancers are the most common human tumors encountered worldwide. The majority of GI cancers are unresectable at the time of diagnosis, and in the subset of patients undergoing resection, few are cured. There is only a modest improvement in survival with the addition of modalities such as chemotherapy and radiation therapy. Due to an increasing global cancer burden, it is imperative to integrate alternative strategies to improve outcomes. It is well known that cancers possess diverse strategies to evade immune detection and destruction. This has led to the incorporation of various immunotherapeutic strategies, which enable reprogramming of the immune system to allow effective recognition and killing of GI tumors.

Methods: A review was conducted of the results of published clinical trials employing immunotherapy for esophageal, gastroesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers.

Results: Monoclonal antibody therapy has come to the forefront in the past decade for the treatment of colorectal cancer. Immunotherapeutic successes in solid cancers such as melanoma and prostate cancer have led to the active investigation of immunotherapy for GI malignancies, with some promising results.

Conclusions: To date, monoclonal antibody therapy is the only immunotherapy approved by the US Food and Drug Administration for GI cancers. Initial trials validating new immunotherapeutic approaches, including vaccination-based and adoptive cell therapy strategies, for GI malignancies have demonstrated safety and the induction of antitumor immune responses. Therefore, immunotherapy is at the forefront of neoadjuvant as well as adjuvant therapies for the treatment and eradication of GI malignancies.

Figure

Immunotherapeutic strategies. (A) Vaccine-based immunotherapy. Vaccination leads to the presentation of peptides on major histocompatibility complex (MHC) classes I and II molecules of antigen-presenting cells, such as dendritic cells (DCs), to stimulate antitumor CD8⁺ and CD4⁺ T cells, respectively. Activated CD4⁺ T cells send costimulatory signals to induce full maturation of DCs and activation of CD8⁺ T cells. Activated CD8⁺ T cells migrate to the site of tumor and mediate tumor killing. (B) Monoclonal antibody therapy. Injection of monoclonal antibodies leads to antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), or apoptosis by blockade of required growth factors and signals. Alternatively, monoclonal antibodies bind to immune cells to enhance immune responses. (C) Adoptive cell therapy. Immune cells isolated from the peripheral blood, tumor, and/or lymph nodes are activated in vitro with high-dose interleukin-2 (IL-2). High numbers of activated immune cells are injected back into the patient to mediate tumor cell cytotoxicity.