Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models

Abstract

At the turn of the last century, the emerging field of medical oncology chose a cytotoxic approach to cancer therapy over an immune-centered approach at a time when evidence in support of either paradigm did not yet exist. Today, nearly 120 years of data have established that (a) even the best cytotoxic regimens only infrequently cure late-stage malignancy and (b) strategies that supplement and augment existing antitumor immune responses offer the greatest opportunities to potentiate durable remission in cancer. Despite widespread acceptance of these paradigms today, the ability of the immune system to recognize and fight cancer was a highly controversial topic for much of the twentieth century. Why this modern paradigmatic mainstay should have been both dubious and controversial for such an extended period is a topic of considerable interest that merits candid discussion. Herein, we review the literature to identify and describe the watershed events that ultimately led to the acceptance of immunotherapy as a viable regimen for the treatment of neoplastic malignancy. In addition to noting important clinical discoveries, we also focus on research milestones and the development of critical model systems in rodents and dogs including the advanced modeling techniques that allowed development of patient-derived xenografts. Together, their use will further our understanding of cancer biology and tumor immunology, allow for a speedier assessment of the efficacy and safety of novel approaches, and ultimately provide a faster bench to beside transition.

Keywords: canine cancer models; checkpoint blockade; history of immunotherapy; mouse models of cancer; patient-derived xenograft models; tumor immune evasion.

Figure 1

Patient Derived Xenograft (PDX) mice for the evaluation of cancer immunotherapies. PDX mice are generated by surgical transplantation of small, non-disrupted pieces of primary human lung tumor under the skin of lymphocyte-deficient NSG mice. This allows the human tumor to engraft, vascularize, and grow in the immune deficient mice, the periphery of which repopulate with co-transplanted human tumor-associated immune cells that can successfully be targeted with experimental immunotherapy. These immunotherapies can be tailored to tumor-specific pathways of immune exhaustion if immune phenotyping, transcriptomics, or proteomics can be performed on the same tumor. Further, tumors from P0 mice can be excised and these explants transplanted into new NSG hosts (P1). This process can be repeated (P2) to generate ever-larger cohorts of tumor-matched mice. While each PDX transplantation cohort is increased in size, the human immune cells which co-transfer with tumor transplantation, are diluted and eventually lost, abrogating investigative abilities to test immunotherapy approaches that target the endogenous patient-derived immune repertoire. However, pharmacological and chemotherapeutic testing targeting tumor cells directly can still be performed. *endogenous immunotherapy targeting the patients own immune cells.