Joshua Brody, MD, director of the lymphoma immunotherapy program at the Tisch Cancer Institute at Mount Sinai in New York City, who wasn’t involved in the research, said he doubts that sensitization would apply broadly across all types of therapy. For instance, CAR-T treatments, which effectively wipe out a person’s endogenous T-cell repertoire before engineered T-cells are reinfused, would be unlikely to benefit from ICI therapy prior to CAR-T administration, he said.

Nevertheless, the idea that ICIs could be improving responses to treatments such as certain chemotherapies, is “exciting,” Dr Brody said. “We should be thinking not that these medicines don’t work [at all] for non Hodgkins, but that they don’t work so far.”

Dr Diefenbach and her colleagues proposed several mechanisms by which sensitization could occur. One hypothesis posits that ICIs could alter the tumor microenvironment, shifting it from a tumor-tolerant environment to a more cytotoxic one. That alone may not be enough to activate T cells to start killing tumors. But once chemotherapy begins to damage the tumor, allowing infiltration of T cells — all while triggering expression of diverse antigens across cancer cell surfaces — “then you have these activated immune cells that could finally go to work, and work with the chemotherapy to eradicate the lymphoma,” Dr Diefenbach noted.  

She and her colleagues hope for prospective studies that investigate how tumor microenvironments change before and after ICI treatment to help untangle the underlying mechanism of sensitization. “You can even in the lab potentially do synergy studies in animals or in vitro to understand how to sequence these drugs or how they may synergize.”


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The sensitization effect itself also needs to be validated in prospective clinical trials, Dr Ansell noted. A trial could randomly select patients to receive ICIs followed by chemotherapy, or a different treatment followed by the same chemotherapy. However, such a study could be hard to accrue patients for, given that the upfront treatment of NHL with ICIs is known to be ineffective. A different approach could be to combine chemotherapy with ICIs and compare efficacy with chemotherapy alone.

Studies testing such approaches for other malignancies are under way, but some analyses are already exploring their utility in NHL. A general challenge in combining chemotherapy with ICIs, however, is that chemotherapy kills immune cells, including T cells that have been primed with ICIs. To address that issue, Dr Brody and his colleagues recently explored a new approach, combining ICIs with an “immunotransplant,” which involves extracting T cells prior to chemotherapy and reinfusing them afterward.8

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In this way, researchers could protect the ICI-primed T cells from the chemotherapy, while also taking advantage of homeostatic proliferation — that is, the process by which T cells transferred to lymphodepleted recipients rapidly divide and become activated, Dr Brody explained. Mice that underwent this combination treatment lived much longer than mice treated with ICIs alone, and the treatment was effective against several tumor types, including NHL.

These preclinical findings have motivated the launch of a multicenter, open-label clinical trial (ClinicalTrials.gov Identifier: NCT03305445) in patients with relapsed/refractory DLBCL, who will receive dual ICI therapy with ipilimumab and nivolumab followed by extraction of T cells and reinfusion following a lymphodepleting chemotherapy regimen. Another trial is exploring combination ICI with radiotherapy for NHL patients (ClinicalTrials.gov Identifier: NCT03789097). Both aim “to get around some of the hurdles with [ICI]” in NHL, Dr Brody remarked.

Disclosure: The investigators disclosed various financial ties to the pharmaceutical industry in this study. For a full list of disclosures, please refer to the original paper.

References

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