Immune-based therapies in pancreatic and colorectal cancers and biomarkers of responsiveness

Abstract

Immune-based strategies are the most promising treatments to improve cancer disease control. Early clinical trials are ongoing to test the safety and feasibility of immune-based therapies for gastrointestinal cancers. However, to date, immunotherapy has been only an experimental option for these diseases and a better understanding of their molecular, cellular, structural and clinical dissimilarities is crucial in the generation of tailored immunotherapeutic treatments. In this review, we will summarize the key mechanisms that regulate the action of immune system in cancer and the different immune-based approaches aimed at improving disease control in patients with advanced disease. We will then move on to discussing the current immunotherapeutic approaches in two types of gastrointestinal (colo-rectal and pancreatic) cancers, whose immune microenvironment has been lately object of intense analyses and has emerged as an important determinant of clinical outcome.

Keywords::

• biomarkers
• colo-rectal cancer
• immunotherapy
• pancreatic adenocarcinoma
• tumor microenvironment

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Immunotherapeutic approaches are a valid alternative to unsuccessful conventional treatments. Antigen specificity and memory are key features of the immune system that confer immune-based approaches for the cure of cancer with the potential to induce long-lasting protection for all cancers.

• Measurement of the immune response induced by immune-based strategies in peripheral blood does not reliably reflect the patient’s clinical response. This observation confirms that the local microenvironment plays a major role in determining whether the immune-based strategy will be effective. Distinct immunotherapeutic approaches should be adopted, according to the features of the tumor immune microenvironment. Moreover, it represents a source of biomarkers of responsiveness.

• The microenvironment of pancreatic cancer is highly immunosuppressive and inhibits the generation of an effective antitumor immune response, therefore representing a target of immunotherapeutic approaches, which might redirect the dysfunctional immune microenvironment in an effective antitumor immune response.

• Current available treatments for pancreatic cancer have failed to demonstrate long-term benefit in patients with advanced disease. The efforts of immune-based approaches are directed towards both an early detection of pancreatic cancer, as well as the treatment of advanced diseases. Some of these approaches are showing significant results.

• Colorectal cancer is highly infiltrated by adaptive cells with antitumor properties and correlating with better patient outcome. This feature has propelled the development of immune-based strategies, which, however, up to now are mostly restricted to the use of monoclonal antibodies.

• Since the introduction of cancer vaccines in clinical practice, the need for immune biomarkers of therapeutic efficacy and that can help identifying patients who can benefit of immune-based approaches has become a priority. Guidelines for the development and use of biomarkers in immunotherapy trials have been provided by the iSBTc-SITC/FDA/NCI Taskforce; they indicate how to establish, standardize and evaluate immune assays, so that they meet a biomarker designation [81].

• Clinical response to immunotherapies can manifest with a longer kinetic compared to chemotherapy. This discrepancy has prompted the research and definition of criteria for response to cancer immunotherapy, which have been named immune-related response criteria.

• Combinatorial approaches potentiating the antitumor immune response while targeting immunosuppressive circuits are currently being tested in preclinical models and fast translation to clinic is expected in the future.

• Despite being considered promising approaches to the cure of cancer, the patentability of immunotherapeutic strategies has encountered several problems, which have resulted in an initial lack of interest and funding from pharmaceutical companies. The major obstacle has been the development of valid assays to monitor immune response, which can dramatically change from patient to patient and that has hindered clinical development. However, recent encouraging results of clinical trials may have changed this scenario and opened a new era for cancer immunotherapy, as indicated by the high number of immunotherapy patents available in databases and confirming that the field is under active investigation.