Steven Eric Finkelstein, MD
Chief Science Officer 21st
Century Oncology Scottsdale, AZ
Radiation-driven immunotherapy (RDI) is an exciting area of research where evidence is accumulating suggesting that this biological process may have important ramifications for the future of clinical radiotherapy.
In patients undergoing radiation, the complex interplay of tumor cell death, antigen expression, inflammatory signals, and lymphocyte and dendritic cell (DC) activation presents a unique therapeutic opportunity. Together, the whole therapeutic effect can exceed the sum of its parts and can present the potential for further improvement of immunotherapy effects arising from tumor irradiation to generate RDI—in effect providing immunologic- mediated, radiation-driven personalized systemic therapy.
The fundamental mechanism of tumor control through radiotherapy is through induction of DNA damage in cancer cells. However, this view is not a complete picture of the time course of cellular events within the tumor. There are associated changes in the microenvironment, tumor-associ- ated endothelial cells, inflammatory infiltrates, and systemic responses to the tumor destruction.
Areas of higher dose exposure inside the bulk of the tumor may have markedly different pathways to cell death, emphasizing necrosis mechanisms. Additionally, the time course of changes of antigen expression during the cell-killing process and differences among radiotherapy techniques can be relevant.1
Several events have been studied for their specific immunotherapy relevance beyond the phenomenon of cells dying within the radiated tumor. Some of the downstream events relate to inflammation and clearance of antigens within the irradiated volume; those of most interest influence acquisition of a more activated general or more activated tumor-specific phenotype. The most dramatic outcome is when a distant tumor mass regresses as a consequence of this, known as the abscopal effect. Examples of this effect are described in case reports2-4
and preclinical studies,5
which have led to recently completed clinical trials.6-12
Other less apparent outcomes as a consequence of the radiation-triggered immune activation include acceleration or completion of definitive clearance of the irradiated tumor or clearance of microscopic or other metastatic disease that was not clinically apparent.
Incorporating RDI Into Therapy Indeed, there are abundant opportunities to transform the phenomenon of radiotherapy-induced anticancer immune response from the realm of isolated case report into a predictable, directed therapeutic goal. What are the key components to make this a reality?
Priming the System
One component is the understanding of how to use systemic therapies to transform the host lymphocyte compartment and antigen-presenting cell compartments so that they become primed to be stimulated. Some examples of immune modulators with the potential of having a significant impact on the phenotypes of the DC compartment include TLR9 agonists,13,14
all trans retinoic acid,15
and inhibitors of VEGF, TGF-β, or of other cytokines.16-18
Comparably, stimulation of the lymphocyte compartment with checkpoint inhibitors (PD-1, CTLA-4) and cytokines also appears poised to make a significant contribution to clinical practice.
Another component is development of further effective ways to provide tumor-associated antigen to the immune system. While recombinant vaccines, tumor lysates, and synthetic peptides have attributes of convenience and definable antigen sets, they cannot be considered interchangeable with tumor irradiation as a source. Unique features of tumor irradiation include simultaneous elaboration of subtle microenvironmental changes with the capacity to improve antigen presentation, total tumor as a source of antigen, production of radiation-induced antigens, and provision of antigen even before overt or immediate cell killing occurs.