Understanding and Harnessing the Immune Effects of Cryoablation: A Work in Progress

Apart from the appeal of cryoablation as a minimally invasive alternative to surgery, many women are drawn to cryoablation because of its potential to stimulate an anti-cancer immune response. Their interest is understandable. Afterall, if we can turn the immune system into an effective anti-cancer force, we would have truly found the elusive “magic bullet.” However, before you completely abandon conventional anti-cancer therapy like anti-estrogen medications and/or chemotherapy, it’s important to understand that there is no definitive proof that cryoablation consistently generates an anti-cancer immune response that is strong enough and sustainable enough to be reliably protective against cancer recurrence.  

To be sure, the absence of proof of a beneficial response does not mean that a beneficial immune response does not occur. As Aldous Huxley put it, “I’m too much of a skeptic to deny the possibility of anything.”  Still, a cancer patient must be wary about placing all of her survival “eggs” in the immunotherapy “basket” without convincing proof that cryoablation can achieve the desired immune benefits.

We in the breast oncology community know that breast cancer cells are crafty and adaptable.  By virtue of being living cells, they are capable of evolving in response to new stresses and developing resistance to specific therapies. That’s the main reason why “standard” cancer therapy always combines multiple complimentary treatments to attack cancer cells from different vantage points. Immunotherapy is just another potential tool in the cancer armamentarium that is not expected to eliminate the need for all other therapies.

Although I am among the strongest proponents of cryoablation, I also feel the obligation to caution the public that at the present time, enthusiasm about the immune benefits of cryoablation greatly exceeds the evidence that it happens in a reliable way in human cancers.  Indeed, there are multiple examples of cryoablation of human cancers producing improved cancer control. However, for every successful case of beneficial immune response there a greater number of examples where an effective, generalized, protective anti-cancer effect was not achieved. This leaves us wondering which patient or tumor specific factors distinguish responders from non-responders.

The most compelling evidence to support a generalized, systemic anti-cancer response comes for animal studies that demonstrated disappearance of lung metastases in mice after cryoablation of their primary tumors. Unquestionably, these are a really exciting findings, but the reality is that we’ve “cured” cancer in mice many times over without successfully translating these successes into human cures. This speaks to the challenge of reproducing in humans research results obtained in the ideal environment of animal experiments where nearly every factor is controlled, including the animals’ genetic make-up. Still, these animal studies show us what is possible, at least in theory, and inspires us to work harder to achieve the same results in humans.

The medical journal article that I have selected for the January 2020 feature at www.cryoablation.com provides a comprehensive overview of what is currently known about the immune effects of cryoablation in various cancer types. The “take home message” from the journal article is that we have just begun to “scratch the surface” in understanding the immune effects of cancer cryoablation and have much to do to harness and promote its immune benefits. Consequently, there is great need for a broader selection of cryoablation cancer clinical trials and an even greater need for patient participation in cryoablation cancer clinical research. It is also clear from the journal article that a robust, sustained, beneficial immune response to cryoablation will likely require use of  pharmacological agents or other therapies that are capable of enhancing specific aspects of the natural immune response. Use of immune system helpers might be particularly important in specific breast cancer or certain types of breast cancer that are not already immunogenic as evidence by the absence of an existing population of immune cells in the vicinity of the cancer.  

Based on animal studies that cryoablation may facilitate an anti-cancer immune response, several medical practices around the world are currently offering cryoablation in combination with various forms of immunotherapy consisting of drugs or human cell lines. Unfortunately, nearly all of these practices are administering immunotherapy agents outside of the structure of formal controlled clinical trials and without the ability to objectively assess effectiveness and safety. Thus, these practices may benefit financially by marketing occasional treatment successes without acknowledging or even understanding if treatment successes or failures had anything to do with the agent administered. The lack of well-designed clinical trials is also why so few research studies are listed on www.clinicaltrials.gov on www.cryoablation.com. I challenge the places offering cryoablation combined with immunotherapy to conduct proper prospective clinical trials followed by publication of their outcomes for consideration and critique by their peers. They have a responsibility to science and an even greater obligation to trusting, vulnerable patients to conduct appropriate clinical trials to assess the effectiveness and safety of the remedies they offer. As it relates to medicine, I agree with Carl Sagan’s view that “extraordinary claims require extraordinary proof.” Put differently, we should bring at least the same degree of skepticism to claims of cryoablation and/or immunotherapy “cures” as we bring to anything else that “seems too good to be true.”

In an effort to be part of the solution and not just part the problem, I have initiated a cryoablation research plan that will continue to unfold in the coming years. The first has already been completed—the creation of www.cryoablation.com--which I hope to establish as a central clearinghouse of evidence-based information, clinical trials, and publications about breast cancer cryoablation. It will also provide a forum to facilitate communication between members of the lay public who have either undergone breast cancer cryoablation or are considering undergoing breast cancer cryoablation.

The next step is to introduce new breast cancer cryoablation clinical trials. For example, I have already started developing a clinical trial investigating the use of cryoablation in the management of ductal carcinoma in situ (DCIS) or non-invasive (Stage 0) breast cancer. This will be followed by additional trials examining the immune effects of cryoablation in DCIS and invasive breast cancer.

I also intend to form a U.S.-based cooperative group that will bring together stakeholders to develop and participate in multicenter clinical trials aimed at understanding and harnessing the immune effects of cryoablation. In some ways, this new cryoablation organization will resemble the TARGIT Collaborative Group (TCG), a national organization I established years 4 years ago to develop, advocate for, and conduct collaborative research on targeted intraoperative radiotherapy for breast and other cancers.  

For cryoablation, the stakeholders will be clinicians who perform cryoablation or administer immunotherapy, basic scientists capable of conducting immunotherapy studies, patients interested in accessing cryo-immunotherapy clinical trials and funding research, and pharmaceutical companies capable of manufacturing immunotherapy agents as well as sponsoring cryo-immunology research. Each of these stakeholders has a vested interest in seeing cryo-immunology emerge as an effective tool in the cancer armamentarium.

If we can definitively prove that cryoablation has the dual effect of killing breast cancer while also enhancing the anti-cancer immune response (with or without the assistance of drug or other treatments), then cryoablation could one-day achieve each of the following:

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1) Provide an effective alternative to surgery for selected patients with early stage breast cancer;

2) Serve as an initial treatment administered prior to or in conjunction with chemotherapy and/or anti-estrogen therapy for later stage cancers whether or not surgery is planned; or

3) Offer an alternative to surgery for someone with stage IV (distantly metastatic) disease, combined with drug therapy.

The effort to achieve the first goal is already well underway, but things are just beginning for the second and third goals. To accelerate these broad objectives, I invite you to support cryoablation by participating in, advocate for, and funding cryoablation and cryo-immunology research.

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