Immune checkpoint inhibitor therapies (ICIs) have transformed the treatment landscape in several types of cancer, most notably in Hodgkin lymphoma, where response rates as high as 75% have been achieved with programmed death receptor-1 (PD-1)–inhibiting antibodies.1

But for reasons that are unclear, ICI efficacy has been largely disappointing in non-Hodgkin lymphoma (NHL). For instance, in one phase 2 trial in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), fewer than 10% of patients responded to nivolumab, a PD-1–blocking antibody.2 .

Yet a recent retrospective, multicenter study examining how patients with relapsed/refractory NHL who had progressed on ICIs fared with subsequent therapies hinted towards a potential use for checkpoint blockade in NHL. The research, published in May 2020 in the British Journal of Hematology, suggested that ICIs may be sensitizing patients to later-line therapies, possibly offering a new therapeutic approach for NHL patients with advanced disease.3

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“I think it does [suggest] that maybe the immune system is sort of being reprogrammed to some degree,” noted Stephen Ansell, MD, PhD, a professor of medicine at the Mayo Clinic in Rochester, Minnesota, who wasn’t involved in the study. “This is an interesting hypothesis that needs to be evaluated and tested.”

Studies in other malignancies such as non-small cell lung cancer and squamous cell carcinoma of the head and neck have hinted that ICI therapy can sensitize patients to subsequent chemotherapy.4,5 Following some suggestions in the literature that patients with Hodgkin lymphoma also appear to have better outcomes with chemotherapy following treatment with ICIs, Catherine Diefenbach, MD, practicing physician and director of the clinical lymphoma program at New York University Langone’s Perlmutter Cancer Center, and her colleagues wondered whether ICIs could also sensitize patients with NHL to subsequent therapies.6

Their study included 59 patients with relapsed/refractory NHL treated at 17 centers in the United States and Canada who were administered ICIs as a second- or later-line therapy between 2012 and 2017 and then received a different treatment. The majority of patients had advanced disease, predominantly DLBCL. Patients had received a median of 3 therapies prior to ICIs; 97% of patients had then been administered a PD-1 or PD-L1 inhibitor, in most cases nivolumab or pembrolizumab. In 90% of cases, ICI therapy was discontinued because of disease progression.

Following ICI discontinuation, 49% of patients received cytotoxic chemotherapy, 30% got targeted therapies, and 17% received treatment in clinical trials, with 1 patient undergoing stem cell transplant conditioning and another, chimeric antigen receptor T-cell (CAR-T) therapy.

Unsurprisingly, only 5 patients (10%) showed a response to ICI itself. However, 51% of patients saw a response to later-line therapies — a figure that compared favorably to documented response rates for salvage therapies, especially given that the patients had been heavily pretreated before receiving ICIs, the authors noted.

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Intriguingly, patients tended to experience a much longer duration of response (DOR) to post-ICI therapy compared with the line of therapy prior to ICI. For instance, in patients who achieved stable disease after their post-ICI therapy, the median DOR was 310 days, significantly longer than their DOR to pre-ICI therapy (79 days). To the researchers, this suggested that ICIs could be priming the patients’ immune systems in a way that leads to a better response with subsequent therapies.

“It appeared to have a significant impact on how patients responded to their subsequent therapy,” Dr Diefenbach remarked. In fact, this effect was observed regardless of whether the patients responded to ICI treatment or not. Dr Diefenbach and her colleagues have also reported similar findings for patients with Hodgkin lymphoma.7  

In the NHL study, the effect appeared to be independent of the type of post-ICI treatment, suggesting a general sensitization effect — although the authors noted that the small sample size for some therapies made a robust assessment across treatments impossible.