1. Immunotherapy: T-cells and humanized antibodies
It has been known for a century that immunosuppression dramatically elevates the risk of cancer development. The immune system is hence truly critical for patrolling the body fighting off aberrantly proliferating cells. In fact, around 80% of all cancer deaths in metastatic carcinoma, non-accessible by available therapeutics, might be cured by effective immunotherapies.
"Immunotherapy, also called biologic therapy, is a type of cancer treatment that boosts the body's natural defenses to fight cancer. It uses substances made by the body or laboratory to improve or restore immune system function."
Most of the anti-cancer effects elicited by the immune system are mediated by cytotoxic T-cells. One of the presenters at the AACR 2019, Professor Steven A. Rosenberg (NCI, Bethesda, MD, USA) shared encouraging progress on individualized T-cell transfer therapy of treatment-resistant carcinomas.
Professor Rosenberg stressed the critical importance of immunogenic mutated proteins specifically expressed within the patient's own tumor cells, better known as neoantigens. For truly individualized anti-cancer immunotherapy, tumor-infiltrating T-cells (TILs) are extracted from each patient's cancer.
The tumor-reactive TILs are then selected, expanded ex vivo, and reinfused into the patient hoping that they will have become properly selected for their tumor aggressiveness with the ability to combat the tumor.
One fascinating clinical case presented showed sustained regression of metastatic breast cancer and complete response after 39 months of treatment with T-cell transfer immunotherapy.
The development of biologics (humanized antibodies) to break immune checkpoint inhibition, mainly by blocking PD-1/PD-L1 has revolutionized the clinical progress of the field. As with most other oncological therapies, the enthusiasm has in part been moderated by the development of treatment resistance. Looking at the tumor-infiltrating T-cells it seems that their tumoricidal property is confined to a subtype of CD8+ T-cells with a "stem-cell-like" gene signature, producing IFN-γ and which is responsive towards anti-PD-1 treatment.
As for the innate of the tumor microenvironment, one of the presentations emphasized the anti-tumorigenic M2 macrophages and their conversion into tumor-fighting M1-macrophages in vivo by the PI3K-γ inhibitor IPI-543 (Infinity Pharmaceuticals) presently in Phase I clinical trial against several solid cancers such as lung cancer and melanoma.
Much attention was given to bi-specific humanized antibodies, that of hybrid antibodies able to target sites for concerted attack by effector T-cells. These synthetic antibodies have been engineered to simultaneously bind to the surface of the tumor cells and a common component of the T-cell receptor making the killing of the tumor cells exceedingly efficient. One of several examples is that of CD20-TCB (RGG6026) which is a novel T-cell engaging bi-specific antibody that has been shown to induce complete remission in relapsed non-Hodgkin lymphomas in an early clinical trial.