Biological bases of cancer immunotherapy

Abstract

Immunotherapy has changed the landscape of cancer treatment and has significantly improved the outcome of several cancer types including breast, lung, colorectal and prostate. Neoantigen recognition and immune checkpoint inhibitors are nowadays the milestones of different immunotherapeutic regimes; however, high cost, primary and acquired resistance and the high variability of responses make their extensive use difficult. The development of better predictive biomarkers that represent tumour diversity shows promise because there is a significant body of clinical data showing a spectrum of immunotherapeutic responses that might be related back to their specific characteristics. This article makes a conceptual and historical review to summarise the main advances in our understanding of the role of the immune system in cancer, while describing the methodological details that have been successfully implemented on cancer treatments and that may hold the key to improved therapeutic approaches.

Keywords: Cancer; immune checkpoint; immune modulation; immune responses; immunotherapies; neoantigen.

Fig. 1.

Immunotherapeutic Clinical Trials started during 20th century worldwide. Number of clinical trials per year for the four most common cancer types: breast, lung, colorectal and prostate cancer. Data extracted from the ClinicalTrials.gov database according to the following search strategy: (a) study type: interventional studies, (b) status of study results: all studies, (c) additional criteria: study starts from 01/Jan/1990 to 30/Nov/2020 (data updated until 1/Dec/2020).

Fig. 2.

Immunomodulatory targets for cancer treatment. Some immunomodulatory agents currently in clinical trial status for breast, lung, colorectal and prostate cancer were shown in this picture. Its effect on the immune cell population is described briefly. Each arrow symbolizes a stimulating/potentiating effect on immune cell effector functions, whereas the truncated lines represent an inhibitory effect on effector response related to the molecule. Immunotherapeutic protocols are designed to induce or blockade the activation of the pathways related to the molecules shown. Therefore, the action of immunotherapeutic approaches on each molecule is represented by (+) or (−), according to its activating or inactivating role, respectively. Also, dotted lines indicate a secreted compound. These data were extracted from the ClinicalTrials.gov database, according to the following parameters: (1) study type: interventional studies, (2) recruitment status: not stopped studies (i.e. not yet recruiting, recruiting, enrolling by invitation, active not recruiting and completed), (3) study results: all studies, (4) study start: from 01/Jan/2010 to 04/Dec/2019. APC, antigen-presenting cells; DC, dendritic cell; NK, natural killer.

Fig. 3.

Immunotherapeutic clinical trials based on neoantigens. Current immunotherapeutic strategies based on tumour neoantigens were listed. In the picture, neoantigens proposed for clinical trials on breast, lung, colorectal and prostate cancer were summarised, the most advanced clinical trial phase (I–IV) is shown in parentheses. Similarly, several neoantigen vaccination strategies applied in the clinical trials are shown. These data were extracted from the ClinicalTrials.gov database, according to the following parameters: (1) study type: interventional studies, (2) recruitment status: not stopped studies (i.e. not yet recruiting, recruiting, enrolling by invitation, active not recruiting and completed), (3) study results: all studies, (4) study start: from 01/Jan/2010 to 04/Dec/2019. CAR T cell, chimeric antigen receptor T cells; DNA, deoxyribonucleic acid; Dribble, tumour-derived autophagosome vaccines; FPV, fowlpox virus; HPV, human papillomavirus; L. monocytogenes, Listeria monocytogenes; MVA, modified vaccinia Ankara; RNA, ribonucleic acid; S. cerevisiae, Saccharomyces cerevisiae; SLiPs, long-lived proteins; VRP, virus replicon particle.