New immunotherapeutics aren’t working well when combined with standard forms of care

A newly published article in the journal Science Translational Medicine has questioned the merits of treating prostate cancer patients with immunotherapies while they are simultaneously being treated with medical forms of castration (androgen deprivation therapy or ADT), chemotherapy, and/or radiation therapy.

There is strong logic behind this argument. We know that radiation therapy, chemotherapy, and medical forms of ADT (as opposed to surgical forms of ADT, i.e., orchiectomy) all suppress the immune system to some degree and are therefore acting contrary to the concept of boosting immune function that underlies immunotherapy. However, at least in man (as opposed to in laboratory tests and animal studies), we have very limited data as to the effectiveness of any immunotherapies used to date in the management of prostate cancer when they are initiated on their own.

The paper by Yu et al. — and a supporting media release from the University of Texas Southwestern Medical Center — base their argument on data from mouse models of prostate cancer treatment, but turning such a premise into a medically effective strategy for prostate cancer treatment and care of real prostate cancer patients in the real world is probably going to be a great deal more difficult.

There is no doubt that the timing of immunotherapy is a key factor in how well it is likely to work in the treatment of prostate cancer. If immunotherapy was going to work really well, one might expect the optimal use to be shortly after first-line treatment of men with intermediate- and high-risk prostate cancers, when boosting the immune system might reasonably be expected to lead to the elimination of any residual cancer cells or clones. Unfortunately — at least to date — we have not seen this type of major response in either the large Phase III trials conducted to seek approval for some types of immunotherapy or in other smaller trials.

By the time men have demonstrably metastatic disease, we also have limited data to demonstrate the impact of immunotherapeutic agents used on their own in the treatment of later stage forms of prostate cancer. By contrast, we have excellent data from the STAMPEDE and the CHAARTED trials that very clearly demonstrate the benefits of combining ADT with chemotherapy and radiation (although it is absolutely true that almost all such patients will relapse again at some point in the future).

The senior author of the new paper, Dr. Xang-Xin Fu of the University of Texas Southwestern Medical Center, is quoted as stating that:

We hope that our findings will cause physicians to think twice before starting chemotherapy or radiation on their cancer patients, to consider the best way to combine them with immunotherapies. The idea is to kill tumor cells while also considering whether these therapies are suppressing or activating the immune system.

Dr. Fu’s logic is 100 percent accurate. But if we are to be able to turn his logic into really practical forms of treatment and care for men with prostate cancer, we are going to need to see some much better outcomes data for prostate cancer patients treated with immunotherapeutic agents as monotherapy than anything that The “New” Prostate Cancer InfoLink is currently aware of. Unless immunotherapy can be used to place men into long-term remission (or at least a stable disease state) without combining its use with things like ADT and radiation (let alone chemotherapy), then why would one initiate the immunotherapy at all?

6 Responses

  1. You state … “We are going to need to see some much better outcomes data for prostate cancer patients treated with immunotherapeutic agents as monotherapy.” Could you please inform us of examples of clinical trials that employed immunotherapy as primary monotherapy? I’m unaware of any. If there were numerous such trials, is there a review article on the topic? Thanks.

  2. I think we have to be very careful to explain that this was just a single mouse study that demonstrated that a GnRH antagonist (e.g., degarelix) — but not a GnRH agonist (e.g., leuprolide) or physical castration — showed a unique biochemical mechanism that reduced a certain immune response.

    Inexplicably in the UT Southwestern press release, Dr Fu took his very particular mouse-study finding and generalized it well beyond GnRH antagonists in mice. I have to disagree with his unfounded statement that “the upshot is that some chemotherapies and radiation therapies should not be used concurrently with immunotherapies.” So far, the bulk of clinical evidence is in the opposite direction. In fact, in a commentary last year, we examined evidence to the contrary.

    There are several clinical trials running now to test the hypothesis that there is a synergistic effect between radiation, chemotherapy, and immunotherapy. A few exploring the synergy between radiation and immunotherapy are mentioned in our commentary.

    There are several clinical trials exploring the synergy between chemotherapy and immunotherapy. Last year, a pilot trial (n = 25) in humans demonstrated that, compared to Taxotere alone, an immunotherapy called DCVAC/PCa given before and after chemotherapy, led to a 66-74% lower risk of death based on historical nomograms. Based on those impressive results, an expanded Phase III trial (n = 1,170, 158 locations) called VIABLE is ongoing and is expected to report results in 2018.

    In 2006, NIH reported some favorable favorable findings from a pilot trial of ProstVac + Taxotere in metastatic castrate-resistant men. They are now recruiting for another pilot trial of ProstVac + Taxotere in metastatic hormone-sensitive men.

    While, given the early evidence to the contrary, the statements in the press release are unfounded and irresponsible, it may be true that GnRH antagonists may not be the best AR-suppressor to use in immunotherapy cocktails. However, even this very limited finding is far from proven by a single mouse study.

  3. I should also direct interested readers to a commentary last year on a lab study that demonstrated a biochemical mechanism by which sub-lethally irradiated cancer cells activate an enhanced immune response. Radiation and immune activation seem to make good bedfellows.

  4. Dear Len:

    There have only been a few very small trials of immunotherapy as monotherapy that I am aware of — and rarely if ever as a first line therapy. I am sure this has all been reviewed somewhere, but I haven’t looked for such a paper. You could try searching PubMed for “prostate + cancer + immunotherapy + review” (or similar) and see what you could find. There were, on the other hand, large trials of GVAX several years ago as adjuvant monotherapy after first-line treatment of high-risk patients (I think with either surgery or radiation therapy) in an attempt to get GVAX approved for that indication. They were unsuccessful.

    My point is simply that there are no really meaningful data (that I am aware of) showing that immunotherapy as monotherapy is particularly effective in the management of any stage of prostate cancer (yet).

  5. This raises another issue re. immunotherapy treatment. At what disease stage is it currently available?

    Since Provenge appears to be the only immunotherapy approved outside clinical trials for prostate cancer (please correct me if I’m mistaken), it is only covered by insurance once a man is castrate resistant.

    From recent experience, men diagnosed with well advanced disease who rapidly become castrate resistant may have too high a tumor burden to make Provenge effective or relevant.

    This research suggests perhaps they should get Provenge as soon as they are diagnosed … and certainly that is true for men with a lower tumor burden.

    All very confusing and frustrating.

  6. Rick D:

    The Provenge FDA-approved indications are even more restrictive than that. The patient must be metastatic, asymptomatic or minimally symptomatic, as well as castrate-resistant. Thank God for clinical trials!

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