Potentiating checkpoint inhibitors (PD-1/PD-L1) by adding a local ablative treatment

[D.ap]

I’ve been reading on immune therapy and the combining of different ablative techniques (RFA,MWA) studies and results in reference to synergy response away from the the treated tumor and I was wondering why you all choose radiation over cyro and or microwave treatment ?
Will it possibly create the most necrotic response ?
I’ve been just starting to understand the delicate need/balance that the medical professionals are seeing needed to create the very best immune response ,to not only the treated ablated tumor but the remote tumors as well. The adjunctive treatment to the immune therapy if you will. It’s quite a delicate balancing of how to best elicit the very best orchestration of the dying tumor (ablation)and the immune Med, so as the immune system is in gear to clean up the necrotic material by recruiting immune T cells, so they attack the damaged cancer tumors both at the ablated tumor and the “damaged “ remote cancer cells. Causing a systemic
Immune response.

[Olga]

Deb, all these local treatment ablative modalities (RFA, cryo, other percutaneous types, radiation) produce a very complex immune response to a dying tumor - it depends on dosage, regimen, metastatic site, patient's own immune make up, tumor type make up, mets size etc. There are similarities and differences in the tumor's and body response to the local treatment modalities. There are numerous pro-inflammatory and other signaling substances that are secreted as a response to these local treatment modalities, and then they start to interact with the ones that are in the tumors and in the body and a cascade of the events starts and it is getting modified as the times goes. There are also immune supressive factors like TRegs that form in the later stages of this cascade. Its interaction with the immune check point inhibitors like PD-1 and PD-L1 drugs that block PD-1 or PD-L1 expression depends on the all of it and a timing. The overall understanding of the process and the interaction between two treatment modalities is poorly understood as of now, with multiple clinical trials underway combining radiation with the immune check point inhibitors (make a search on the Pubmed "radiation pembrolizumab" to see what is there). In the beginning we were thinking of a cryoablation of that met. I found an article where the immune response to cryo was measured and there is a very big inter-patient variability to cryo - the response ranges from immune supressive to neutral to immune stimulating, so there is a risk to cause an opposite effect. With the radiation therapy there is less variability and more predictable immune stimulating response in the first inflammatory of the treatment response. Besides you need to find a doctor willing to participate in a non-proven treatment, and multiple clinical trials performed for the radiation+immunotherapy combo make it psychologically easier for the doctors to agree. Few clinical trials in melanoma shown a very increased efficacy for both, radiation and immunotherapy in a combo although it might be tumor specific. We have a file with the review written and I might post it later somewhere appropriate. I haven't done it yet because it is all really unproven. There are some hints that both treatment should be done simultaneously or very close to each other and a radiation should be hypo-fractionated (few treatments only) and relatively high dose - like 3-5 treatments with 8-10 Gy per a fraction.

[D.ap]

Thank you Olga for the explanation .
A lot of complex factors .

I also understood the 3 possibilities of reponses being sent by T cels ,with any combination of immune therapies and locoregional therapies. The tumors can become protected by the immune system, be attacked , or be neutral .
It’s partly antigen driven ?
( see introduction in following link)

http://www.cureasps.org/forum/viewtopic ... coregional

Will the radiation be performed before or after infusion ?

My very best thoughts and prayers for success coming your way , with the upcoming radiation treatment and infusion ..

[Bonni Hess]

Thank you for your thoughtful sharing dear Debbie. This is very interesting and important information to be aware of, especially for those undergoing Immunotherapy treatment and especially during this heightened cold and flu season when antibiotics are often prescribed. With special gratitude, caring thoughts, and continued Hope, Bonni