Immune biomarkers: how well do they serve prognosis in human cancers?

Abstract

In order to be optimally efficacious, therapeutic cancer vaccines must induce robust tumor-specific CD8⁺ cytotoxic T cells, which are responsible for tumor cell lysis. Unlike cytotoxic drugs, which act directly on the tumor, cancer vaccines demonstrate new kinetics involving the generation of specific cellular immune responses, which need to be translated into antitumor responses to delay tumor progression and improve survival. These delayed kinetics of action establish a new concept of benefit in the long term, which implies a slow down in tumor growth rates, than a marked reduction in tumor size. Therefore, there is a significant need to identify intermediate biomarkers so that clinical responses can be evaluated in a timely manner. Therapeutic vaccination as a modality for cancer treatment has received significant attention with multiple clinical trials demonstrating improvements in overall survival. Significant challenges to this modality remain, including increasing vaccine potency and minimizing treatment-related toxicities and identifying prognostic and predictive biomarkers of clinical benefit that may guide to select and optimize the therapeutic strategies for patients most likely to gain benefit.

Keywords:

• biomarkers
• cancer immunotherapy
• cancer vaccines
• gene signature
• immune monitoring
• immunoediting
• tumor infiltrating lymphocytes

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

• Therapeutic cancer vaccination comprises a series of immune reactions to either induce or activate T cells, thus promoting T-cell infiltration into the tumor, followed by tumor regression.

• Identifying immunologic biomarkers would help not only guide the development of immunotherapy trials, but also act as surrogates for clinical benefit.

• For improving clinical outcome, further to increasing vaccine potency and minimizing treatment-related toxicities, it is imperative to recognize prognostic/predictive biomarkers of clinical benefit.

• Intratumoral immune measures may serve as prognostic and predictive biomarkers for overall survival and response to treatment, respectively.

• The heterogeneity of tumors resulting from the immunoediting process, but also obstacles in the standardization of assays measuring cellular immune responses, contribute to inconsistencies in the identification of uniform biomarker signatures.

• The numbers and functions of circulating T lymphocytes in cancer patients during and after immunotherapies have been also analyzed as potential biomarkers.

• The AE37 vaccine paradigm proposes considering pre-existing systemic TGF-β levels and IFN-γ immunity to the vaccine both as prognostic for overall survival and predictive factors for responses to vaccination. Delayed-type hypersensitivity reactions to the vaccine have also been found to correlate with clinical benefit.

• The tumor cell selection process subjected to uniform immunological pathways during the later stages of immunoediting may provide a common biomarker profile as a prerequisite for tumor progression paving the way for therapeutic options.

• Prospective validation of biomarker signatures defined in small-scale clinical trials in large Phase III studies is absolutely necessary.

Notes