Exploring New Frontiers in Cryoablation and Immunotherapy Synergy

See also article by Wehrenberg-Klee et al in this issue.

Delmarie M. Rivera Rodríguez, MD, is a research fellow in the interventional radiology department at Northwestern University. Her research interests include interventional oncology, minimally invasive procedures, and the development of innovative therapeutic techniques. With a strong commitment to advancing the field of interventional radiology, she actively contributes to studies aimed at improving patient outcomes and expanding treatment options.

Samdeep K. Mouli, MD, MS, is an associate professor of vascular and interventional radiology at Northwestern University Feinberg School of Medicine. He specializes in interventional oncology. Dr Mouli completed his medical degree and master of science at Northwestern, followed by residency in diagnostic radiology and fellowship in interventional radiology. Currently, he is dedicated to advancing innovative therapeutic techniques and contributing to research and education in interventional radiology and oncology.

Checkpoint inhibitory immunotherapy (CPI) has recently gained substantial attention as an emerging targeted treatment in oncology. This therapy harnesses the immune system’s ability to recognize and eliminate tumor cells, targeting immune checkpoints (such as programmed cell death protein 1 [PD-1], programmed death ligand 1 [PD-L1], and cytotoxic T-lymphocyte–associated protein 4 [CTLA-4]) and critical pathways that tumors co-opt to evade immune surveillance (1). By blocking these inhibitory pathways with therapeutic antibodies, checkpoint inhibitors unleash a more robust and sustained antitumor immune response. While some CPIs have been approved for various cancers, including hepatocellular carcinoma (HCC), many patients do not respond adequately to these therapies. Even when effective, the responses may not be curative. In particular, liver metastases have shown resistance or a poor response to immunotherapies (2). Moreover, CPIs are associated with adverse events, highlighting the need for strategies to enhance efficacy while limiting additional severe immune-related toxicities. As a result, recent efforts have focused on combining immunotherapy with localized treatments to overcome immune resistance and amplify antitumor immunity. Cryoablation has emerged as a promising candidate to achieve this goal. The ablation modality not only facilitates tumor destruction but also releases tumor antigens and inflammatory signals, stimulating systemic immune responses. The immune response triggered by cryoablation alone is often insufficient, as tumors can still exploit immune checkpoints to evade destruction (3). Nonetheless, the combined treatment strategy of cryoablation and CPI offers a possibility to overcome these limitations and achieve durable antitumor effects (3). By leveraging the localized destruction of tumors along with the resulting immune activation, these combined therapies present an exciting frontier in oncology.

In this issue of Radiology: Imaging Cancer, Wehrenberg-Klee et al (4) explore this synergy, aiming to assess the effect of adjunctive partial cryoablation on the response to CPI. Their work addresses long-standing clinical interest in inducing the abscopal effect, a phenomenon in which tumors outside the local treatment area also shrink or disappear. The abscopal effect has been observed rarely when cryoablation is used in isolation (5,6). The authors hypothesize that adjunctive cryoablation may be particularly beneficial in tumors with high mutation rates by enhancing the exposure of tumor antigens to antigen-presenting cell surveillance. Furthermore, their study aims to investigate how cryoablation could be advantageous in conjunction with dual-agent CPI, which promotes both adaptive immune system priming and sustained cytotoxic T-cell activity.

The growth of immunotherapies has been accompanied by a deeper understanding of the underlying mechanisms of CPI and its effects on tumor microenvironments. Recent research highlights that while the kinetics of response to checkpoint inhibitors can differ significantly from traditional therapies, often resulting in delayed responses, these therapies can lead to long-lasting effects even after treatment cessation (7). This unique response pattern is partly attributed to the development of immunologic memory, where the immune system retains the ability to recognize and target cancer cells even in the absence of ongoing treatment. Furthermore, the recognition of immune-related adverse events as potential markers of clinical benefit underscores the complex interplay between treatment efficacy and immune activation (8). Such adverse events, which may arise from heightened immune responses, can indicate that the immune system is effectively engaging with tumor antigens, suggesting a robust antitumor response (8). This phenomenon has prompted researchers to further investigate the relationship between these events and positive clinical outcomes, enhancing our understanding of how to optimize treatment strategies in cancer immunotherapy.

Wehrenberg-Klee et al (4) reiterate these concepts in their work. In the study, the researchers utilized murine models to evaluate the effects of combining cryoablation with dual checkpoint inhibitors, specifically anti–CTLA-4 and anti–PD-1. Two tumor lines, MC-38 and CT-26, were implanted into the flanks of C57BL6 mice. Each mouse was randomized to receive either vehicle control or specific doses of the checkpoint inhibitors. Interestingly, the authors modified their cryoablation technique from that of conventional methods. Rather than cryoablating the entire tumor, as is standard clinical practice, they ablated only approximately 50% of the tumor. The rationale behind this choice was to preserve some vascular and lymphatic architecture to facilitate more rapid trafficking of antigen-presenting cells and more efficient sampling of tumor antigens than complete cryoablation. Other studies have characterized the method of partial cryoablation and applied it in clinical practice, yielding relatively positive results, such as the combination of tremelimumab (anti–CTLA-4 antibody) and ablation in patients with advanced HCC, which demonstrated encouraging tumor response rates and the accumulation of intratumoral CD8⁺ T cells (9). However, some retrospective analyses raise concerns about tumor progression in patients who experience incomplete ablation, indicating that, while incomplete ablation may not significantly affect overall survival, it is associated with a higher risk of tumor progression compared with complete ablation (10).

Results of the study indicated that in MC-38 injected mice, survival rates significantly increased when combining checkpoint inhibitors with adjunctive cryoablation. Specifically, the survival rates at 60 days were 0% for vehicle or cryoablation alone, while they reached 61% for CPI-only and 79% for CPI with cryoablation. These results align with other preclinical studies supporting cryoablation as an adjunctive therapy to checkpoint inhibitors across a wide range of malignancies such as renal cell carcinoma, non–small cell lung cancer, and breast cancer (2,3,11). The findings collectively suggest that the combination of checkpoint inhibitors and cryoablation effectively delays tumor growth and enhances antitumor immune responses by counteracting immunosuppressive effects of the tumor environment and amplifying the immune response triggered by cryoablation.

Prior studies reported that adjunctive therapies can enhance the immune response, allowing for a more robust attack against tumors (2,11). The authors also address the complexities involved in optimizing the timing and method of cryoablation relative to CPI, suggesting that their modified approach (targeting only a portion of the tumor) may improve antigen presentation and immune activation. This may be of clinical utility in settings where complete ablation may not be feasible due to tumor size or location. Furthermore, they acknowledge the limitations of their study design, such as the challenges in modeling metastatic disease with subcutaneous tumors, while advocating for further research to elucidate the biologic mechanisms at play and to identify which patients might benefit most from these combined therapies.

These findings raise important questions. What mechanisms contribute to the increased survival observed with cryoablation in conjunction with checkpoint inhibitors? Are there optimal parameters for cryoablation that maximize its synergistic effects with immunotherapy? Additionally, how can we mitigate the risks associated with incomplete ablation, which some studies have suggested could lead to tumor progression? Certainly, the authors’ work seems to raise questions that will inspire further research, offering an exciting step forward in developing combination therapies that hold promise for improving cancer treatment outcomes, particularly in patients who may not fully respond to checkpoint inhibitors alone.

Wehrenberg-Klee et al (4) highlight a promising direction in oncology with systemic and local therapies, where combining checkpoint inhibitors with partial cryoablation offers the potential to improve therapeutic outcomes. By integrating localized tumor destruction with systemic immune activation, this approach not only enhances response but also opens the door to novel combination therapies that could benefit patients who do not fully respond to CPI alone. As further research explores the optimal parameters for cryoablation and its synergistic potential with immunotherapy, this strategy may play a critical role in the next generation of immunotherapy protocols leveraging the added benefit of local ablation.