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.

NK cells and CTLs are required to clear solid tumor in a novel model of patient-derived-xenograft

“…Current PDX models lack a human tumor-donor-matched, complete, functional and mousetolerant immune system (53)(54)(55)(56)(57). One PDX model relies on serial transplantation of solid tumors into NOD/SCID/IL2Rγ c -KO (NSG) mice to maintain genetic tumor diversity and allow for the evaluations of tumor genetics and chemotherapies (66).…”

“…One PDX model relies on serial transplantation of solid tumors into NOD/SCID/IL2Rγ c -KO (NSG) mice to maintain genetic tumor diversity and allow for the evaluations of tumor genetics and chemotherapies (66). However an infusion of donor-matched or mismatched PBMC is required for immune system reconstitution, which results in the development of graft versus host disease (GvHD) within weeks of infusion (53). To circumvent GvHD, the second PDX model was generated by infusion of umbilical cord derived hematopoietic stem cells (UB-HSC) into immune compromised mice before tumor is engrafted, resulting in the development of mouse tolerant T cells (53).…”

“…Existing PDX models lack a human tumor-donor-matched, complete, functional and mousetolerant immune system (53)(54)(55)(56)(57) and, consequently, lack the utility for specific types of cancer immunotherapy and mechanistic studies. To fulfill this unmet need, we developed a PDX model of human solid tumor with a syngeneic complete mouse tolerant and functional immune system that reconstitutes recipient mice for at least six months post tumor engraftment, is responsive to combination immunotherapy and allows for in depth mechanistic in vivo studies.…”

Adaptation of the group A Streptococcus adhesin Scl1 to bind fibronectin type III repeats within wound‐associated extracellular matrix: implications for cancer therapy

“…Developed by Dr. William Coley, a bone sarcoma surgeon (1862–1936), Coley's toxin was the first use of a cancer immunotherapy in medicine (Burdick, ; McCarthy, ). Coley and colleagues injected live and killed streptococci to treat patients afflicted with soft tissue and bone tumors with relative success (Decker et al , ). Interestingly, we now know that osteosarcoma cells express cFn isoforms that contain EDA and/or EDB, as well as TnC (Kilian et al , ; ; Sun et al , ).…”

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…The early laboratory development of immune checkpoint inhibitors (ICIs) has been reviewed in detail by others . In brief, James Allison and his colleagues were the first to outline the critical function of cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) as a negative regulator of T‐cell activation .…”