Immuno-oncology recapitulates ontogeny: Modern cell and gene therapy for cancer

Immuno-oncology (IO) has had over a century to develop from the original seminal insights of Virchow in 1863, seeing inflammation and lymphoid infiltrates as a common anlage for many adult tumors. That IO has become a central pillar of cancer treatment has come about because of the remarkable clinical and subsequent commercial success of immune checkpoint blockade (ICB) in the last 15 years. This now includes approved cell and gene therapies for patients with cancer, including an armed adenovirus, oncolytic herpesvirus, and adoptive transfer of dendritic cells, chimeric antigen receptor T (CAR-T) cells, and tumor-infiltrating lymphocytes (TILs). The evolution of such applications has required the stepwise development of a deeper understanding of the molecular biology of cancer and the physiology of immunobiology. This also recapitulates, in a broader sense, our evolutionary trajectory with capture of "evolvability," not only across the development of species but also within individuals. This review covers how our foundational understanding of immune system learning and evolvability have facilitated better understanding of the co-evolutionary interactions between the epithelium and the immune system. We highlight examples of this in breast, colon, prostate, pancreas, and lung cancer, and provide examples of next-generation cell and gene therapies that intercept cancer development.