Science to Practice: Can We Expand Focal Interventional Oncologic Ablation Treatments into an Effective Systemic Therapy?

Abstract

Hamamoto et al were able to demonstrate that combination therapy of a lung tumor by using radiofrequency ablation with local injection of an immunostimulant, OK-432, resulted in improved survival when compared with other therapies tested in a VX2 rabbit model.

Summary:

Hamamoto et al (1) were able to demonstrate that combination therapy of a lung tumor by using radiofrequency ablation (RFA) with local injection of an immunostimulant, OK-432, resulted in improved survival when compared with other therapies tested in a VX2 rabbit model. In addition, not only was greater tumor regression seen in a second distant ear tumor implanted prior to the therapy, but also reduced tumor growth was seen when a second tumor implantation (ie, rechallenge) was attempted. These factors strongly suggest the successful activation of systemic antitumor immunity using this approach in this specific tumor model.

The Setting

Conventionally, interventional oncologic therapies, particularly percutaneous ablation, have been thought of as local, focal treatment (2). Thus, much of the current literature deals with the barriers of successfully treating tumors larger than 3 cm in diameter with any of the available energy sources (eg, radiofrequency, microwave) and methods for treating larger tumors (particularly combination therapies with chemoembolization and drugs delivered by nanocarriers such as liposomes) have received much attention. Nevertheless, there is ever increasing awareness of more global systemic effects that occur secondarily from tumor and tissue ablation, including elevation of serum cytokines, liver regeneration, and changes in distant tumor proliferation (3,4). Given that such systemic effects do invariably occur to some degree with many, if not all, of our treatments, a fundamental understanding and appreciation of all of the potentially beneficial and deleterious effects that may result from our interventions is warranted. Indeed, a greater mechanistic understanding of these phenomena may very well enable us to not only prevent untoward consequences of our ostensibly local treatment, but also enable us to take advantage by accentuating any potentially positive effects (5). Within this framework, the study by Hamamoto et al adds to our knowledge of how we can take advantage of the immune effects generated by ablation by using an adjunctive therapy that has been previously introduced into interventional radiologic practice as a sclerosant of vascular malformations (6).

Conceptually, the investigators began with the phenomenon that an “abscopic effect” of systemic tumor shrinkage is occasionally seen following ablation (4,7). They connected this observation to published studies showing favorable alterations of RFA on systemic immunity, including those that have shown that RFA of tumor releases a small quantity of tumor antigens that are ultimately presented to T lymphocytes by dendritic cells to induce activated tumor-specific T lymphocytes (8). Next, in keeping with prior studies showing that that amplifying these pathways can create an enhanced antitumoral response (9), they sought to find an adjuvant sufficiently robust to be therapeutically useful. Accordingly, they identified OK-432, an immunostimulant prepared from the penicillin-inactivated low-virulence strain Su of Streptococcuspyogenes (group A) that has been shown to antitumor immunity in experimental animal models by activating tumor-specific T lymphocytes, and hypothesized that RFA-induced systemic antitumor immunity could be enhanced indirectly by adjuvant local injection of OK-432.

The Science

Hamamoto et al (1) designed a relatively straightforward set of animal experiments to answer the question of whether antitumor immunity is enhanced systemically by combining RFA with the local injection of an immunostimulant, OK-432. Although many prior studies have demonstrated immune-mediated responses (either through increased cell activity and/or infiltration or rechallenge studies), and changes in tumor growth and/or regression of unablated residual tumor around the local tumor treated with ablation, here the authors created an experimental design that enabled them to demonstrate three different effects in the same model. First, they conducted a randomized four-arm study of VX2 tumors injected in two sites, the lung and the ear, including: a control group (supportive care), RFA, direct intratumoral injection of OK-432, and a combination therapy consisting of OK-432 injection 1 week after RF ablation. As therapies were only performed on the lung tumor, this double implantation strategy enabled them to elegantly and readily assess effects of the ablation and immunotherapy not only locally, but also on a remote tumor.

The investigators documented a doubling of their primary endpoint, median survival time, with combined therapy to 105 days compared with either single therapy alone (37 and 47 days for RFA and OK-432, respectively), which translated to nearly a fivefold increase in survival compared with controls (23 days). Implied by these results is the fact that combination therapy reduced both primary and potentially metastatic disease common to this model. Furthermore, they showed that over 7 weeks of follow-up the second implanted auricle tumor also decreased in size only for the combination therapy group (from a maximum of 339 to 115 mm³). Given that the distant untreated tumor increased in size for all other comparison groups (although slower for both the RFA and OK-432 groups compared with the control group), the beneficial systemic effect for this double treatment was clearly demonstrated.

Next, the authors performed a tumor challenge study, implanting VX2 on the ear of the rabbits, and showed that reimplanted tumors reduced in size after 1 week compared with reimplantation in control animals, a finding previously noted in several other animal models (4). Interestingly, animals receiving RFA alone also showed similar reductions in tumor size at rechallenge and a slower auricular tumor growth rate, again proving some modest immune effect of RFA alone in the VX2 model (10).

The Practice

Clinical use: Performing high-quality translational research with an eye toward rapid clinical implementation continues to be a key and necessary strength of interventional oncology. Fortunately, a main strength of this study was the investigators’ selection of technology (both in the form of the agent, OK-432, and method of delivery–direct, image-guided intratumoral injection) that is already in active clinical use. Indeed, several prior studies on immunomodulation with RFA, while methodologically elegant, used adjuvants that themselves would require years of development prior to incorporation into clinical practice (4). Yet, clearly, confirmation of these results in animals with well-designed clinical studies is paramount prior to widespread introduction of any specific combined therapy approach. Given that activation of the immune system can potentially be a double-edged sword, a balance of sufficient immune stimulation to treat the tumor without achieving overstimulation and paradoxical increased tumor growth will be a primary concern. Nevertheless, if these goals were to be successfully attained, achieving systemic antitumoral effects would be met with substantial enthusiasm as a key perceived weakness of ablation therapy–its local nature–would potentially be obviated.

Future opportunities and challenges: While the potential future opportunities and impact for extending image-guided techniques to achieve not only local, but also systemic effects are legion, as the investigators note there are many additional hurdles that must be overcome before the use of ablation to induce purposeful beneficial systemic immunotherapy for cancer becomes a clinical reality. Optimization of the immunostimulants in terms of the correct agents, dosage, and timing based on dynamic changes in the postablation immune and inflammatory environment will be necessary. This must be further tailored to specific ablative energy sources as other energy sources such as microwave and irreversible electroporation and cryoablation may have different levels of response as the extent and type of inflammatory and/or immunologic response may differ (11). Indeed, it is conceivable that other ablative techniques may ultimately prove a better match for immune stimulation, or that other methods of altering innate or adaptive immunity will be more apt for RFA treatments. Beyond all of these considerations lies a primary consideration–the proper matching of these system components to the biology of both the tumor and host. This undoubtedly includes the need to study a wide range of tumor types, many of which will invariably express different levels of immunogenicity than the VX2 model, where immunologic effects may play a greater or reduced role. Within this framework, the call for additional basic research that will improve our understanding of how our ablation techniques influence the immune system, including a better understanding of actual cytokinetic mechanisms and cellular interactions, almost appears redundant. Ultimately, how the concept of using immunostimulant adjuvant therapy to potentiate ablation will fare currently remains an open question that is well worth answering.

Disclosures of Conflicts of Interest: S.N.G. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: consultancy for Cosman Company and Angiodynamics; grants/grants pending to author’s institution from Cosman Company and Angiodynamics. Other relationships: none to disclose.