THE "NEW" PROSTATE CANCER INFOLINK

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.

Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: immunotherapy, radiation, radio-immunotherapy |