Radio-immunotherapy in the treatment of prostate cancer

Starting today, we have a new contributor to the content of The “New” Prostate Cancer InfoLink.Allen Edel has a particular interest in and knowledge about radiation therapy in the management of prostate cancer, and will focus on offering information about developments in this field. His first contribution is on the topic of radio-immunotherapy, which is the combination of radiation therapy with various possible types of immunotherapy. It holds potential in the treatment of a wide variety of cancer types, prostate cancer included.

Finkelstein et al. have written an excellent review of the current understanding of the emerging and complex field of radio-immunotherapy. In contrast to some earlier studies that showed that radiation depressed the gamut of white blood cell types (e.g., Johnke et al., 2005), recent studies have shown that any such radiation-induced leukocyte suppression in high-risk men is temporary, and there is a long-lasting enhancement of the anti-cancer immune response. The discrepancy with earlier findings may be due to the higher doses of radiation used now, or the higher-precision radiation fields. There is also some evidence that the effect may vary with the kind of prostate cancer (the phenotype), the different prostate cancer risk levels, and the way the dose of radiation is administered (e.g., low-dose brachytherapy vs stereotactic body radiation therapy [SBRT]).

In fact, Finkelstein et al. find the opposite of the conventional wisdom to be true: radiation has an immune-stimulatory effect when used in treatment of men with high-risk prostate cancer. There is an opportunity to bolster this effect when treating high-risk men with radiotherapy — in initial prostate radiation, salvage radiation after surgery, lymph node radiation, or radiation to isolated metastases. If this effect is maximized, there is a hope of killing off systemic micrometastases and tumors well outside of the radiation field. This is called the abscopal or bystander effect.

Radiation kills cancer cells, and the cellular debris is a source of antigens. Dendritic cells learn to use those antigens to activate killer T cells that then seek out and destroy cancer cells elsewhere that express those antigens. The damaged cancer cells also signal a host of other tumor-toxic molecules to form. Radiation-modified cancer cells that escaped direct annihilation become more immune-susceptible too.

Sipuleucel-T (Provenge), a dendritic cell boost coupled with immune-stimulatory factors, seems to be a perfect companion to radiation. There is a randomized clinical trial (NCT01807065) currently recruiting at the City of Hope National Cancer Center in Los Angeles to determine whether sipuleucel-T’s effectiveness is enhanced by radiation to a single metastasis in men with metastatic, castration-resistant prostate cancer (mCRPC).

But immune stimulation will never be long lasting. Eventually, the immune system will regard the cancer cell as if it were a normal healthy cell of one’s own and will stop attacking it. To continue the attack, a different sort of immune encouragement is required. These so-called “checkpoint blockers” are currently represented by drugs like ipilimumab (Yervoy) and pembrolizumab (Keytruda) that have been FDA-approved for use in other forms of cancer.

Ipilimumab + radiation therapy for mCRPC has been tried in two pilot tests. In one of these studies, patients were given radiation to a single bone metastasis followed by ipilimumab or a placebo, but the addition of ipilimumab did not significantly increase survival. A larger study (NCT00861614) has been completed, and we are awaiting results. In another study, patients were randomly assigned to get ipilimumab + radiation or ipilimumab alone. Both the patients’ PSA levels and the response of the bone metastases were good, and about the same for both groups. A new immunotherapy, ProstAtak, is being tested with radiation for localized prostate cancer (NCT01436968).

Some have suggested that several hypofractionated doses of radiation maximize the immune effect. To that end, researchers at the University of Virginia have initiated a clinical trial (NCT02284971) of an experimental immune stimulant, varlilumab, coupled with SBRT in five doses to the prostate and/or metastases in men with CRPC.

Other immune stimulants, like Leukine, have been used effectively in mice, and by some clinicians in human patients. It is likely that the optimal combination of immunotherapy with radiation therapy will include a front-end stimulant and a back-end checkpoint blocker. Adding androgen blockade may enhance the immune effect still further (see Antonarakis and Drake), and radiosensitize the tumors.

9 Responses

  1. That looks truly interesting, but, terminologically speaking, radioimmunotherapy has a different meaning, i.e. treating with a radioisotope attached to an antibody.

  2. Allen,

    It’s great to see you sharing your knowledge here. A fine Christmas present to all of us.

    As a high-risk patient treated in my 14th year as a survivor last year with 39 sessions of TomoTherapy including a pelvic dose (26 sessions), I found your comments most interesting.

  3. Herb, that’s probably true — I hope you’ll forgive the shorthand. It’s easier than writing “the synergistic combination of radiotherapy and immunotherapy.”

    Jim, thanks! I know that many have been inspired by your long-term progress, and I hope you will continue to add your insights to the commentary on this site.

  4. Great to see you adding your wisdom to the Brains Trust at TNPCIL, Allen.

    This post is particularly interesting w.r.t. Snuffy’s recent videos that left many of us scratching our heads. It offers an excellent counterpoint, and I will post this link on Inspire.

    Tx Allen and Happy New Year

  5. Rick,

    I’ve heard that Dr. Myers did a video about it, although I haven’t watched it. It’s very hard for me to respond when people are speaking off the cuff like that. I wish he would cite sources for his data, so that we all could better respond.

    Happy and healthy New Year to you!

  6. I haven’t seen Snuffy’s video as yet. I read the above article with great interest, especially the reference to Leukine as a stimulant immunotheraputic vaccine having been tested on mice and some humans. My husband has been taking shots of Leukine since March, 2014 (Snuffy’s immunotheraputic drug of choice for my husband). Do you have the link to Dr. Myers recent video? I would appreciate it.
    Thanks, Eyden1

  7. The University of Virginia clinical trial that you mention, of varlilumab with SBRT, has three arms:

    — Varlilumab before SBRT
    — Varlilumab concurrently with SBRT
    — Varlilumab after SBRT.

    Why you do think that “the optimal combination of immunotherapy with radiation therapy will include a front-end stimulant”, rather than concurrently with, or post, radiation therapy?

  8. Donna:

    All Dr. Myers videos are available at this link.

    There are two videos that are specifically relevant: one on treating oligometastatic prostate cancer and the other on treating oligometastatic prostate cancer with radiotherapy.

    I have not yet watched the follow-up/clarification.

    Frankly, the first video sounds more like a falling out between Dattoli and Myers than a valid medical observation — especially given that Myers referred many men to Dattoli for years for pelvic girdle radiation while well aware of the issues he mentions as being the reason not to radiate lymph nodes.

  9. PaulAu,

    As I said, I think both front-end stimulant and back-end checkpoint blocker will turn out to be optimal. The trials so far of single immunotherapies for prostate cancer have been good but not great. That’s just my personal opinion. Others are looking at combining two or more. In Augusta, GA, for example, they are combining Provenge, an anti-PD-1 antibody, and low dose cyclophosphamide (NCT01420965). Cancers adapt quickly to the challenges we throw at them. My feeling is that we are better off attacking the cancer on multiple fronts.

    As for the optimal timing, no one yet knows. It seems to me that we want the immune system primed and ready to launch an attack by the time the SBRT blasts cancer antigens into the serum. There may be some lead time for such priming to occur. SBRT is so short (5 treatments, usually) that “during” is not much of a factor — immune stimulation lasts for months. “After” is important because we don’t want the immune system to shut down the attack by learning to recognize the cancer as “self.” It may take months or years for the immune system to find and attack all the cancer cells.

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