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Is cryo-immunology the next frontier for cryoablation? 

Cryoablation represents a frontier in minimally invasive cancer treatment, offering a novel approach to the destruction of both benign and malignant tumors. This procedure leverages extreme cold, applied directly to the tumor site, to induce cell death without the need for traditional surgical removal. The appeal of cryoablation lies in its simplicity and the reduced recovery time for patients. Recent research has raised intriguing questions about the fate of the tumor post-treatment and its broader implications for cancer care. 


Understanding the Cryoablation Process 

At the heart of cryoablation is the precise application of freezing temperatures, a process that unfolds through a series of biological mechanisms. Initially, the formation of ice crystals within the extracellular space and within the tumor cells. Ice crystals formation in the extracellular space leads to osmotic injury, causing cells to dehydrate and shrink during the freeze phases and ice crystals formation within the tumor cells leads to mechanical injury to the tumor cells. This is swiftly followed by cell swelling and rupture during the thaw phases. Moreover, the formation of ice crystals disrupts the structural integrity of cells, compounding the damage. 

Read our blog ‘Cryoablation Cancer Therapy – How Does Tumor Freezing Work?‘ for a more detailed exploration of these mechanisms.   

Beyond the immediate cell destruction, cryoablation also impairs the tumor’s vascular supply. The induced vascular injury results in secondary cell death due to ischemia, depriving cells of essential nutrients and oxygen. Additionally, cells at the periphery of the cryoablation zone are triggered to undergo apoptosis, a form of programmed cell death characterized by systematic cellular disassembly that avoids eliciting an inflammatory response. 

Central to the scientific inquiry surrounding cryoablation is its potential to incite an immunogenic response against the cancer cells. This aspect of cryoablation, still under rigorous investigation, hints at the procedure’s ability to not only destroy the tumor locally but also to mobilize the body’s immune system against cancerous cells, offering a dual front in the battle against cancer. 


Post-Cryoablation: What Happens to the Tumor? 

Following cryoablation, the immediate aftermath within the tumor is a state of necrosis. This form of cell death is characterized by the loss of membrane integrity and the uncontrolled release of cell contents, leading to an inflammatory response. Necrosis is most pronounced within the core of the freeze zone, where temperatures reach their lowest. 

Adjacent to this necrotic core, in the peripheral zones of the cryoablation area, a different process unfolds. Cells here, subjected to less extreme cold, undergo apoptosis rather than necrosis. Apoptosis is a cleaner form of cell death, where cells neatly package their contents into vesicles called apoptotic bodies, which are then safely engulfed and digested by immune cells such as macrophages. This process, known as phagocytosis, ensures that the cellular debris does not provoke inflammation. 

Over time, the necrotic tissue left by cryoablation is gradually resorbed by the body, with phagocytic cells playing a pivotal role in clearing the debris. This natural process of removal and absorption culminates in the replacement of the former tumor mass with fibrous, collagenous scar tissue. Remarkably, this transformation occurs without the need for surgical intervention, allowing the body to heal and recover more swiftly. Patients may initially sense the presence of the tumor area due to the scar tissue, but this sensation typically diminishes as the body’s healing processes continue. 

The Immunogenic Response: A Dual Benefit 

The intrigue of cryoablation extends beyond its ability to physically destroy tumor cells. Emerging evidence suggests that this procedure might also kickstart the body’s immune defense mechanisms, offering a dual advantage in cancer therapy. The phenomenon, known as an immunogenic response, could potentially transform cryoablation from a localized treatment to a systemic therapeutic strategy. 

This immunogenic response hinges on the type of cell death induced by cryoablation. Necrotic cell death, prevalent in the core of the cryoablated area, tends to provoke an immune reaction due to the uncontrolled release of cellular components. These components, including DNA, RNA, and heat shock proteins, can serve as “danger signals” to the immune system, flagging the presence of a threat and mobilizing tumor-specific T-cells. This activation could be crucial in targeting not only the treated tumor but also distant metastases, offering hope for a more comprehensive cancer treatment approach. 

Conversely, apoptosis, which predominates at the cryoablation site’s periphery, generally does not elicit a strong immune response. The orderly breakdown of cells into apoptotic bodies avoids releasing danger signals, potentially leading to an immune-suppressive environment. This differential response underscores the complexity of the immune system’s interaction with different forms of cell death. 


The Impact of Freeze Rate on Immune Response 

The cryoablation procedure’s technical nuances, particularly the rate at which tissue is frozen, can significantly influence the immune response. A rapid freeze rate tends to favor necrosis, leading to a more pronounced immune activation due to the release of cellular contents. This effect is beneficial for stimulating an immune response capable of recognizing and attacking cancer cells. 

In contrast, a slower freeze rate encourages apoptosis, especially in cells at the edge of the cryoablation zone. This form of cell death, characterized by a lack of inflammatory danger signals, may lead to a more subdued immune response or even immune suppression. The balance between necrosis and apoptosis, therefore, is a critical factor in the overall effectiveness of cryoablation as a cancer treatment. 

Furthermore, the extent of tissue necrosis and the resultant immune response can be modulated by the number of freeze-thaw cycles during cryoablation. Multiple cycles can amplify tissue damage and potentially enhance the immunogenic effect. However, the relationship between freeze-thaw cycles and patient outcomes, including survival rates, is complex and not directly proportional, highlighting the need for careful optimization of cryoablation protocols. 


Clinical Evidence and the Abscopal Effect 

The potential for cryoablation to induce systemic immune responses has been a subject of fascination and study for decades. The abscopal effect, a phenomenon where localized treatment leads to regression of distant, untreated tumors, exemplifies the immunogenic potential of cryoablation. Historical observations, particularly in prostate cancer, have documented cases where cryoablation not only reduced the primary tumor but also led to spontaneous regression of metastatic lesions, suggesting an immune-mediated mechanism at play. 

Preclinical models have further supported this concept, with animals treated with cryoablation showing resistance to subsequent tumor challenges, akin to a vaccination effect. Clinical studies, such as those involving hepatic tumors, have reported heightened immune activity and instances of necrosis in tumors distant from the treatment site following cryoablation, reinforcing the procedure’s potential to elicit a broad immunogenic response. 

The exploration of cryoablation’s immunogenic capacity is ongoing, with particular interest in its combination with immunotherapies. This emerging field, termed cryo-immunology, seeks to amplify the immune response initiated by cryoablation, potentially enhancing the efficacy of cancer treatments and paving the way for new therapeutic strategies. 

Advancing Cancer Treatment: Cryoablation and Immunotherapy 

The evolving landscape of cancer treatment is increasingly pointing towards the integration of cryoablation with immunotherapy, a synergy that holds promise for revolutionizing cancer care. Cryoablation, by its very nature, exposes tumor antigens to the immune system in a stark and unprecedented manner. This exposure, however, may not always be sufficient to mount a systemic attack against metastatic diseases.  

To amplify this immunogenic effect, researchers are exploring the combination of cryoablation with a range of immunotherapies, including checkpoint inhibitors like ipilimumab and nivolumab, as well as dendritic cell therapy and adoptive cell transfer strategies involving natural killer (NK) cells and cytokine-induced killer (CIK) cells. These immunotherapies can work in concert with cryoablation, bolstering the immune system’s capacity to detect and destroy cancer cells. This combination approach not only aims to enhance the overall immune response but also tailors treatment to the unique cancer types and immune profiles of individual patients, marking a significant step towards personalized cancer therapy. 


Clinical Evidence Across Different Cancer Types 

The potential of cryoablation combined with immunotherapy is being investigated across a spectrum of cancer types, with each showing unique patterns of immune activation and clinical outcomes. In breast cancer, for instance, clinical trials have highlighted the synergistic effects of cryoablation with checkpoint inhibitors, leading to a more robust immune response against tumors. Similarly, in renal cell carcinoma, the combination of cryoablation with adoptive NK cell transfer has shown promise in eliciting an immune reaction conducive to cancer treatment. 

Lung cancer research has also seen encouraging results from integrating cryoablation with immune stimulants such as NK cell therapy or DC-CIK, showing improved survival rates for patients. Additionally, in the realm of melanoma and non-Hodgkin lymphoma, trials involving dendritic cell therapy and pembrolizumab in conjunction with cryoablation have demonstrated potential benefits in activating immune responses, offering new avenues for treatment. 


Conclusion: The Future of Cryoablation in Cancer Treatment 

Cryoablation is fast increasing in popularity with patients and physicians as a minimally invasive option to surgery. As we have outlined, research is suggesting that the benefits of cryoablation go beyond mere tumor destruction to potentially engage the body’s immune system in a more comprehensive battle against cancer.  

The burgeoning field of cryo-immunology is showing particular promise in treating metastatic cancers. As research continues to unfold, the integration of cryoablation with other immunotherapeutic strategies is poised to offer more effective, personalized treatment options with fewer side effects, particularly for cancers resistant to conventional therapies. 

Looking ahead, the ongoing exploration and understanding of cryoablation’s role in cancer treatment promise to significantly impact the therapeutic landscape, offering new hope for more effective and less invasive treatment options for patients worldwide.