The phase 1 cohort contained a few patients who had exceptional results on the combination of cyclophosphamide, CAR-T, and PD-1 blockade, including 3 patients considered to have achieved a complete response.

“There’s one patient that we gave a very low dose of CAR-T and checkpoint blockade; he survived 16 months with minimal treatment when 6 months would have been a normal expectation for him. He died after 16 months from other complications not from cancer. The second patient is 14 months on treatment, no evidence of recurrence; he is doing well,” said Dr Adusumilli.

The researchers are currently analyzing samples from these patients in the lab to learn more about their responses. Not content with simply combining CAR-T with checkpoint blockade, Dr Adusumilli and his team engineered the CAR construct to contain a dominate-negative PD-1 receptor (DNR),2 which effectively does a similar job as anti–PD-1 immunotherapy —experiments in mice have shown promise, and human clinical trials start next year.

“We are very excited; it’s 10 years of work in my lab finding something to target. We designed the CAR to target tumor and not normal tissue and combined with PD-1. All of these things, previously proven in mice is what we are now able to show in patients,” said Dr Adusumilli.

These results represent one of the first times where both the efficacy and safety of CAR-T have been shown in solid tumors, although Dr Adusumilli is keen to urge some level of caution: “This is a phase 1 trial and we don’t have the long-term data yet, which is our goal. I don’t want to give anyone false hope,” he added.

Aside from these undoubtedly promising, but preliminary, results for a cancer that typically has a dire prognosis, if these early signs of success are backed up with longer-term data, this work could set an important precedent for the use of CAR-T in solid tumors.

“A main reason to be excited about these results is that it opens [up the] possibility of local regional delivery at other sites in the body. I think it’s great that someone was able to show that you can safely and effectively administer cells that can be confined to one region of body and not just migrate in the body,” said Dr Abate-Daga.

CAR T-cells targeting mesothelin have already been tested in trials for the treatment of lung, ovarian, and pancreatic cancers, but with little in the way of promising results.

However, in all of these cases, the CAR-T therapy was injected intravenously. The localized approach tested in this new study on pleural cancers may give these therapies renewed life.

“This approach might be useful for other diseases that express mesothelin, where you can inject locally, but it’s unclear currently whether this will work in other places when injected in a confined anatomical location,” concluded Dr Abate-Daga.

References

  1. Adusumilli PS, Zauderer MG, Rusch VW, et al. Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: safety and preliminary efficacy in combination with anti-PD-1 agent. Presented at: 2019 American Society for Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 2511.
  2. Chen N, Morello A, Tano Z, Adusumilli PS. CAR T-cell intrinsic PD-1 checkpoint blockade: a two-in-one approach for solid tumor immunotherapy. Oncoimmunology. 2017;6(2):e1273302.