Stereotactic Body Radiotherapy Immunological Planning—A Review With a Proposed Theoretical Model

Abstract

In the stereotactic body radiotherapy (SBRT) and immunotherapy era, we are moving toward an “immunological radiation plan”, i.e., radiation scheduling with abscopal effect as a vital endpoint as well. The literature review of part A enumerates the advantages of the intermediate dose of SBRT 6–10 Gy per fraction, appropriate use of dose painting, proper timing with immunotherapy, and the potential of immunoadjuvants to maximize cell kill in the irradiated lesions, found to have improved the abscopal effects. Part B summarizes part A, primarily the findings of animal trials, forming the basis of the tenets of the proposed model given in part C to realize the true abscopal potential of the SBRT tumor cell kill of the index lesions. Part C proposes a theoretical model highlighting tumor vasculature integrity as the central theme for converting “abscopal effect by chance” to “abscopal effect by design” using a harmonized combinatorial approach. The proposed model principally deals with the use of SBRT in strategizing increased cell kill in irradiated index tumors along with immunomodulators as a basis for improving the consistency of the abscopal effect. Included is the possible role of integrating immunotherapy just after SBRT, “cyclical” antiangiogenics, and immunoadjuvants/immune metabolites as abscopal effect enhancers of SBRT tumor cell kill. The proposed model suggests convergence research in adopting existing numerous SBRT abscopal enhancing strategies around the central point of sustained vascular integrity to develop decisive clinical trial protocols in the future.

Immunotherapy and Radiotherapy as an Antitumoral Long-Range Weapon—A Partnership with Unsolved Challenges: Dose, Fractionation, Volumes, Therapeutic Sequence

“…A study that combined immunotherapy with CTLA-4 inhibitors in malignant melanoma with brain metastases showed better results in OS if single-fraction stereotactic radiosurgery (SRS) was performed before ipilimumab administration or concomitantly, relative to the situation in which immunotherapy was initiated before irradiation. The study also highlights a slight tendency towards a benefit of the concurrent administration of radiosurgery and immunotherapy [ 30 , 31 , 32 ].…”

The Evolving Interplay of SBRT and the Immune System, along with Future Directions in the Field

“…This advantage, however, is shadowed by the potential of radiation therapy to destroy the newly infiltrated T cells. As such, the optimal sequencing of SBRT would be one in which the radiation is delivered at doses that allow for vascular disruption which enhances the penetration of drugs that will augment the immunostimulatory effects, as well as enhancing the effects of the immunotherapy agent [ 27 ].…”

“…With respect to optimizing tumor lysis and immunogenicity, radiation dose delivery should maximize the systemic anti-tumor effects, while also minimizing the downstream immunosuppressive effects [ 27 ]. Preclinical and clinical studies indicate that SBRT dosing of radiation therapy in combination with immunotherapy may elicit a more robust activation of the immune system in the tumor compared to conventional fractionation dosing [ 28 ].…”

Overcoming Resistance to Anti-Angiogenic Drugs – Caught in the Web, Have We Lost Sight of the Spider?

“…The general aspects of the role of AAGs vis-a-vis tumor vasculature are dealt with briefly in the published article by the present author [3]. The present paper will focus on and expand on NAG, anti-angiogenics, and proposed strategies to overcome the resistance.…”