“The main differences were that the patients in the favorable response group had T-cell responses against not just mutated antigens specific to patients, but also shared neoantigens common in many tumors. We could see that patients who responded to the therapy could generate these responses and had greater T-cell infiltration too, with these T cells producing IFN gamma,” said Dr Sharma.

Although there was a range of numbers of nonsynonymous mutations between individual tumors, the median TMB in both the favorable and unfavorable cohorts was similar, and TMB was not associated with improved clinical responses to ipilimumab.

“They showed that in these cases of metastatic prostate cancer, there was a low TMB, even in those in the favorable outcome group. They saw that in this type of cancer, having a low TMB does not affect the anti-tumor response and perhaps it shouldn’t be taken into account as in other studies,” said Dr Klampatsa.

As well as having a comparatively low TMB, many of the patients in both cohorts (7/9 in favorable and 8/10 in unfavorable) were pretreated with other therapies prior to beginning the ipilimumab trial, which has been suggested to reduce the chance of immune checkpoint inhibition (ICI) working due to negative effects on immune function.


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“This probably contributed to the low rate of objective response observed. Nonetheless, the encouraging long-term outcomes, including OS, for patients in the favorable cohort with associated immune correlates suggest that utilization of ICI earlier in the disease course may elicit more antitumor response, translating into higher responses, and even better long-term outcome[s],” said Dr Wei.

Eight patients on the trial experienced grade 3 toxicities, most commonly dermatitis and diarrhea, with none experiencing grade 4 or 5 toxicities.

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“Only 38% of patients in this study [were] able to complete 4 planned doses of ipilimumab, and 28% of patients experienced grade 3 or higher toxicity. Patients with [mCRPC] are often elderly, have competing comorbidities, and therefore, have lower reserve to tolerate treatment-related toxicities. Careful patient selection therefore is needed in this patient population,” said Dr Wei.

The researchers have also run a trial in localized prostate cancer2 and now plan to run larger, multi-institutional studies to validate their findings in larger patient cohorts. However, rather than using single agents, they will move to combination strategies with ipilimumab and anti–PD-1 agent nivolumab, with a trial being planned.

“The idea that you should use TMB as a selection criteria is something we need to reconsider in some tumor types … it’s not necessarily the quantity of neoantigens present, it might be the quality. These ‘cold’ tumors shouldn’t be completely ignored by the field of ICI. We tend to rely on monotherapy, but the field needs to move in a different direction to provide benefit to patients with these types of tumors too,” said Dr Sharma.

References

  1. Subudhi SK, Vence L, Zhao H, et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci Transl Med. 2020;12(537).
  2. Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017;23(5):551-555.