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Radiation and Immunotherapy Together

Cancer immunotherapy has been a huge topic in recent years, and deservedly so. But there are some types of tumors that respond much better than others, which means that there are also some that hardly respond at all. A great deal of effort is going into trying to find ways to make these immunologically “cold” tumors respond to checkpoint inhibitors and other such drugs.

One way to do this is through external radiation therapy. For a decade or so now, there have been studies in both animal models and in human patients that show that combining local radiation and checkpoint inhibitors can lead to an effect noticeably greater than either one by itself. The mechanisms for this are complex and varied, but at least some of them, not mutually exclusive, are (1) upregulation of some “neoantigen” proteins in tumor cells as a response to radiation, whose expression then opens them up to recognition by T cells and (2) local release of cytokines and other immune-modulating signals in the tissue that’s been irradiated, which can suppress or reverse the immune-dampening effect of some tumor microenvironments.

This sort of treatment looks like it has the best chance of working against a localized tumor, though, since the tissues that don’t get irradiated don’t show the effects above. What if you could deliver radiation to all the tumor tissue simultaneously? You’re not going to be able to do that very feasibly with external beams, but dosing with radioactive drugs that accumulate more in tumor tissue could do the trick. That’s the subject of this new paper from a team at Wisconsin and Pittsburgh. They’re using NM600, which is a phosphocholine derivative with a metal-chelating group attached at the far end. It tends to accumulate in tumors over normal tissues, which is thought to be due to uptake into lipid rafts on the cell surface (tumor cells generally have larger amounts of  alkylphosphocholines). NM600 has been decorated with a variety of radionuclides in the past – 86Y, 90Y, 177Lu, 225Ac, 64Cu, 89Zr and more, for both therapeutic and imaging applications. In this case, the authors used 86Y to do PET imaging to work out the dosing for 90Y, which is a beta-emitter.

In mouse models of various immunologically cold tumor lines, treatment with checkpoint inhibitors (anti-CTLA-4 antibodies or anti-PD-L1 antibodies, both raised against the mouse proteins), showed no response at all. Likewise, treatment with the radioactive NM600 compound showed no response, either. But combining the two led to over half the mice showing complete response along with tumor-specific T-cell memory. And in mice with multiple tumors, this combination was enhanced even more by simultaneously targeting a single tumor with external radiation as well – better effects than external beam plus antibodies or radionuclide therapy plus antibodies. Importantly, the total radiation dose is low compared to standard radiation therapy – it’s not enough to cause bone marrow suppression in the mice, as compared to tumor-killing levels.

The paper goes into a great deal of detail on the dosing and timing of these interventions, as well as cellular measures of the immunological effects. But the overall result seems clear: the radionuclide therapy alters the tumor microenvironment in ways that make the checkpoint antibodies far more effective. The tumor-killing effects are mediated by T cells, as expected. A limitation of the work is of course the xenograft mouse models, but that overall story looks to have a good chance to real-world examples, especially given the dramatic difference in the combined therapy groups. There are plenty of other experiments to be done (with other radionuclides, for example), but this looks like a strong candidate to start moving towards human trials.

14 comments on “Radiation and Immunotherapy Together”

  1. zero says:

    This should be a subset of a larger field of possibilities, including chemical ‘warheads’ that sensitize tumors with perhaps fewer side effects or off-target damage. Interesting.

  2. Aleksei Besogonov says:

    This might be particularly good target for neutron therapy. Enrich the target tissue with boron and then use neutron beams to activate them.

    1. David E. Young, MD says:

      Yes, Boron Neutron Capture Therapy, the Rodney Dangerfield of the radiation world. I wonder if they can get the reactor back up on Osaka?

      1. RTW says:

        Apparently my post yesterday was lost some where. Anyway – I wanted to add Fred Hawthorne passed away July 8th. He basically established the field of Boron Chemistry, and was a proponent of BNCT. 20 years or so ago – I was interesting in building Boron containing drugs for use in BNCT following some work I had participated in in Radiosensitizers. Even though I am retired from Anti-cancer drug discovery – I still try to keep abreast of the field especially with regards to colon Cancer and metastasis especially seeing as I lost my wife to Stage IV colon cancer. I recall reading of abscopal effects some time ago especially with regards to rectal cancer treatment. Additionally – I remember some members of the Colon Talk forums talking about treatment of their Liver mets using nano spheres containing 90Y. They would map the capillaries to the tumor then inject these nano-spheres to locally irradiate the tumor and cut off blood supply. This seemed to have limited success at the time but I think in light of this paper might warrant a second look at the therapy. Also – I recently saw a news brief via Fierce Biotech by Arlene Weintraub about the use of MAO-I’s to treat solid tumors. Very interesting stuff! See: https://www.fiercebiotech.com/research/old-antidepressants-show-promise-as-immuno-oncology-treatments-melanoma-and-colon-cancer

        1. David E. Young, MD says:

          I have a young woman with liver-only metastases from colon cancer. She is not obtaining a good response from second line chemotherapy. I certain will consider having her get Y90 and follow this up with an immune checkpoint inhibitor.

  3. Siddharth Dasgupta says:

    In 1999 we published a paper on 90Y radiotherapy with City of Hope!
    The experimental results did not quite match the computational prediction, though the trend was correct.
    Glad to see this area of work showing some efficacy.
    https://pubs.acs.org/doi/abs/10.1021/ja983706q

  4. johnnyboy says:

    Just a comment – this is not a xenograft model (human tumour in mouse), but rather a syngeneic (mouse tumour in mouse), more appropriate when looking at immune responses. But your point still stands that there is always a very big bridge to cross between mouse models and the clinic.

    1. Robert K says:

      Great catch. Syngeneic models are necessary to understand the endogenous immune response to tumor and treatment (eg, immunotherapies). A big pet peeves of mine is Academics/Industry folks using immuno-compromised mice in their rodent clinical trials; another drawback is that syngeneic models are often “genetically irrelevant” and bear wildly different genetics to human tumor counterparts. Yin and Yang.

  5. JIA says:

    Hi Derek, I suggest a couple minor clarifications. First, “upregulation of some “neoantigen” proteins in tumor cells as a response to radiation” should probably say “creation and upregulation of”. One of the effects of ionizing radiation is to create double-strand breaks in DNA, which can lead to mutation if not repaired properly by the cellular machinery. So radiation actually creates NEW neoantigens, not just upregulating the expression or ones that already exist.

    Second, “…since the tissues that don’t get irradiated don’t show the effects above.” This is not exactly correct. Search “abscopal effect” in Pubmed to get many articles about the ability of localized radiation to induce shrinkage in distant tumor sites that were not irradiated. This too is related to neoantigens, which are taken up by dendritic and other cells and presented in the lymph nodes to T cells which can then migrate to and attack any tumor site displaying that neoantigen, not just the irradiated sites.

    Unfortunately, the abscopal effect is not well understood and not powerful enough to completely eliminate all tumor metastases, otherwise we would use local radiation more often. But radiation + cancer immunotherapy would presumably boost abscopal effects as well as local ones.
    Thanks.

    1. Derek Lowe says:

      Will do – those are good points!

      1. Brian says:

        We often send patients to our radiation colleagues for “spot welding” on problematic metastatic sites. We’ve been doing it more often with immunotherapy on board for this purpose. It may not be a panacea, but every little bit helps. Thanks for pointing out these interesting results!

        1. David Young says:

          That is exactly what I am doing with some lung cancer patients. I have some who have an excellent response to Immune checkpoint inhibitors but then, 9 to 12 months later find the tumor to “escape” in just one spot. I have that one spot radiated and they go another 9 to 12 months and have a second escape of tumor somewhere. I get that irradiated and then they go one another 9 to 12 months. I think this is a good treatment paradigm.

          1. Does appear to be solid evidence that ICI plus RT enhances outcomes (OS and PFS) in NSCLC. Meta-analysis from Florica et al here https://doi.org/10.3390/cancers13102352

  6. Jim Van Zandt says:

    This reminds me of a paper by Newman et al. (https://www.pnas.org/content/early/2019/12/26/1904022116) observing that “unadjuvanted seasonal influenza vaccines administered via intratumoral injection not only provide protection against active influenza virus lung infection, but also reduce tumor growth by increasing antitumor CD8+ T cells and decreasing regulatory B cells within the tumor.” This was specifically with lung cancer. This suggests to me that the immune system interpreted the flu shot as a generic “trouble in lung tissue” indicator, and so concentrated resources there. Radiation damage may work similarly.

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