Immunotherapy Plus Cryotherapy: Potential Augmented Abscopal Effect for Advanced Cancers

[D.ap]

Sat Oct 27, 2018 5:25 pm

Olga let me know if this article is where it needs to be or if this is off topic: )




Introduction
In the era of molecular medicine, the oncology field still faces many extreme challenges extending survival rates to all stage III and IV cancers with many cancers remaining particularly arduous to treat. Five-year survival rates for lung, liver, and esophageal cancers have hovered around only 15% for decades (1). Other diseases, such as mesothelioma, pancreatic carcinoma, and glioblastomas, have only single digit 5-year survival rates (1). All cancers with distant metastases have less than a 10% 5-year survival. For many of these difficult challenges, new approaches to extend survival are under constant clinical investigation. Herein, we propose a novel approach combining two dependable oncology-based treatment platforms to potentially cause a synergistic immune response to target loco-regional and distant cancer metastases efficiently.

http://www.frontiersin.org/articles/10. ... 00085/full

[D.ap]

I found the explanation of how cyro causes a vaccine type reaction (1965) quite ingenious and also fascionating


“A series of papers by Shulman, Yantorno, Soanes, and Gonder from 1965–1967 illustrated how antibodies elicited by cryosurgery of the prostate gland and accessory tissues release circulating antigens and referred to this process as cryo-immunization and coined the term iso-antigens or self-antigens (10). Soanes, Ablin, and Gonder then published the first case report of three human prostate cancer patients who demonstrated the cryosurgical abscopal effect: regression of distant metastases including lesions of the cervical spine, pulmonary metastases, and left supraclavicular lymph nodes metastases following cryoablation of the primary prostate cancer (11). In the following years, investigations aimed to elucidate the mechanisms and subsequent effect of the immunologic response to cryosurgery. Scientists revealed the clinical benefit of cancer antigens, which stimulate the production of antitumor antibodies, cytotoxic T-cells and produce a robust cytokine response targeted specifically toward malignant cells (12). Review of the literature reveals that there is a highly variable immune response to cryosurgery that is stimulatory or suppressive, representing a finely tuned and orchestrated series of events reaching a homeostatic point between the adaptive and innate immune responses. Manipulating this variable response to favor a more cytotoxic immune response would be highly advantageous.”

[D.ap]

But more importantly the article brings us to current understandings of the benefits of cyroablyion techniques .

“Our hypothesis, however, is not interested in the physical mechanisms involved when cryosurgery causes a reduction in the tumor size of early or later stage cancers, but rather the immunological effect induced by the freezing and breaking of tumors, potentially rescuing a patient whose disease has spread to nearby regional lymph nodes (stage III) or other distant organs (stage IV). Hence, our focus here is on how the combination of cryotherapy, preceded by dual immunotherapy, could result in regression of disease in later stage III and IV cancers. This approach would be a novel use of cryotherapy as it is currently used today to either extirpate or debulk cancers without consideration of its potentially more powerful effect on the progression of the cancer and/or its inhibition of metastatic spread to distant organs.”

[arojussi]

After reading that. (Boy it took time.) I would choose cryoablation for abscopal effect. Of course we need way more research before we can be sure what method is best.

[Olga]

When we were choosing the local ablative strategy to add to the immunotherapy treatment Keytruda Ivan was about to start, I read extensively on the subject. There is a basic article looking at the immune related effect of different ablation modalities (unfortunately they did not incl. the SBRT in the same review). All of them were active, cryo was the most active one. But the problem was that it was inconsistent with big inter patient variability - with large increases and large falls in different patients.

Find Table 3, I was looking at the IL-6 levels as it seems they are needed for the ICI response
Image guided thermal ablation of tumors increases the plasma level of IL-6 and IL-10
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167629/

This subject is not new - it was discussed before by many incl. Drs.Littrup and Dupuy that cryoablation alone can induce both an immunostimulatory and an immunosuppressive effect.
SBRT on the other hand is less active but very consistent if the timing is right, when it is done +/- few days before of the ICI drug administration.
But you can still try the cryo later, if you find the targeted met to treat.
More reading is here:
Immuno-thermal ablations – boosting the anticancer immune response
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644150/

Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802022/

[D.ap]

Hello Olga,
In reference to your above post

This subject is not new - it was discussed before by many incl. Drs.Littrup and Dupuy that cryoablation alone can induce both an immunostimulatory and an immunosuppressive effect.

I was again thinking back to Joshua’s liver ablation in 2015 ,beginning propranolol ( for tremors )and then a dose of sutent ( because of increases in disseminated tumors )..and his success with Opdivo beginning ,a year later in 2016.
A systemic Abscopal affect boosting his immune system , the beginning being primed by the cryoablation procedure .

Whose to say.

“In situ tumor ablation creates an antigen source for the generation of antitumor immunity”

https://pubmed.ncbi.nlm.nih.gov/15173017/

Another great write up on immunostimulatory procedures.

Immunostimulatory Effects of Triggering TLR3 Signaling Pathway — Implication for Cancer Immunotherapy

“A growing interest for studying and understanding immunostimulation based therapeutics’ strategies has increased since, it could stimulate different components of innate immunity and consequently stimulation of adaptive immunity [1-3]”

https://www.intechopen.com/books/immune ... unotherapy

Joshuas liver ablation (corrected to cryoablation 😏)

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