Synergy between radiation of metastases and immunotherapy confirmed


Two clinical trials have now confirmed the abscopal or bystander effect in prostate cancer. These effects occur when cancer cells that are not directly treated are nonetheless killed.

All cancer therapies kill one type of cancer cell or cancer cells in one place. For example, spot radiation only directly kills the targeted cancer, Xofigo only kills actively growing cancer in bone, Lu-177-PSMA only kills cancer that expresses PSMA, ADT only kills cancer that is hormone-sensitive, and docetaxel only kills cancer cells susceptible to death via microtubule stabilization.

When radiation (and chemotherapy) kill cancer cells, 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.

Provenge, a dendritic cell boost coupled with immune-stimulatory factors, seems to be a perfect companion to radiation. Based on data from a small, randomized trial at City of Hope, Twardowski et al. reported equivocal results. They irradiated a single metastasis in men with metastatic, castration-resistant prostate cancer (mCRPC). Progression-free survival was 3.7 months among those who received Provenge after SBRT vs. 2.5 months if they received Provenge without SBRT. This outcome did not reach statistical significance (p = 0.06) on this small sample (about 25 in each arm) or with short follow-up.

However, there are conflicting results. Another small trial randomized 32 mCRPC patients to Provenge + Xofigo or Provenge alone. Xofigo (radium-223 chloride) is a radioactive drug that destroys bone metastases. As reported by Marshall et al., after a median follow-up of 5.3 months:

  • Median progression-free survival was 10.7 months for the combination vs 3.1 months for Provenge alone.
  • The percentage of patients who had a PSA reduction of > 50 percent from baseline was 33 percent for the combination vs 0 percent for Provenge alone
  • The percentage of patients who had an alkaline phosphatase reduction of > 30 percent from baseline was 60 percent for the combination vs 7 percent for Provenge alone
  • There were no increases in side effects for the combination

It seems that the greater amount of cell-killing from systemic therapy with Xofigo was better able to stimulate an abscopal effect.

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 “checkpoint blockers” are currently represented by drugs that have been FDA-approved for use in other cancers or for tailored indications: Yervoy (ipilimumab, a CTLA-4 inhibitor, commonly referred to as “ipi”) and Keytruda (pembrolizumab, a PD-1 inhibitor). “Ipi”+ radiation for mCRPC has been tried in two pilot tests. In one study, patients were given radiation to only a single bone metastasis followed by ipi or a placebo, but the addition of ipi did not significantly increase survival. In another study, 50 patients were randomly assigned to get ipi + radiation or ipi alone. With short follow-up, both the PSA and the bone metastasis response was good, and about the same for both groups. A larger study of ipi + radiation vs radiation alone in 799 patients showed no effect (except in select sub-groups) after 10 months of follow-up, but…

There was better news after the 799 patients were followed for a longer time. In an update by Fizazi et al., 2.4 years later, ipi did increase survival in mCRPC patients, all of whom already had docetaxel, who received a single dose (8 Gy) of radiotherapy (SBRT) to one or more (up to 5) bone metastases. The effect reversed over time.

  • From 0 to 5 months post-SBRT, survival was 49 percent worse among those who got ipi
  • After 5 months post-SBRT, survival was about 33 percent better among those who got ipi
  • At 2 years, survival was 25 percent with ipi vs 17 percent without ipi
  • At 5 years, survival was 8 percent with ipi vs 3 percent without ipi
  • Ipi drug toxicity caused death in 7 patients
  • The effect was no different for those with ≤5 or >5 bone metastases.

It may be that those who died in the first few months were already beyond being helped, and the ipi toxicity harmed rather than helped them. Indeed, the earlier study showed a benefit in those with better function and no visceral metastases at baseline.  Ipi alone has been found to have no effect on survival of mCRPC patients, even when used before docetaxel (see this link). SBRT to bone metastases has not been shown to increase survival (but this is the subject of ongoing clinical trials). It is encouraging that the combination has some effect.

Adding androgen blockade may enhance the immune effect still further (Antonarakis and Drake), and radiosensitize the tumors.

There are many unanswered questions:

  • Will the abscopal/bystander effect be any better in men who are metastatic but still hormone sensitive?
  • Is the abscopal/bystander effect maximized with both dendritic cell enhancement and checkpoint blockade, or is the combination too toxic? Does Keytruda work better than Yervoy?
  • What is the optimal timing of radiotherapy and immunotherapy? Should Provenge be used before, during, or after radiotherapy?
  • For how long is the abscopal/bystander effect sustained?
  • Is there still an abscopal/bystander effect when lymph nodes are irradiated?
  • Does the abscopal/bystander effect increase with the number of metastases irradiated?
  • Is there an abscopal/bystander effect with Lu-177-PSMA? (This is the subject of a clinical trial at UCSF.)
  • Will a PARP inhibitor further enhance the abscopal/bystander effect?
  • Can the abscopal/bystander effect be utilized for rare types of prostate cancer (e.g., neuroendocrine or undifferentiated)?
  • Are there any genomics or biomarkers that are predictive or prognostic?

Editorial note: This commentary was written by Alan Edel for The “New” Prostate Cancder InfoLink.

 

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