ABSTRACT & COMMENTARY
Cancer Immunotherapy Dependent on Gut Biome Results from a proof-of-concept trial REFERENCE
Davar D, Dzutsev AK, McCulloch JA, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371(6529):595-602. DESIGN
Proof of concept; open-label trial PARTICIPANTS
Between June 2018 and January 2020, researchers enrolled 16 melanoma patients who had not responded to anti–PD-1 (anti–programmed cell death protein 1) immunotherapy and continued to have progressive disease. STUDY MEDICATION AND DOSAGE
Participants received fecal microbiota transplant (FMT) from patients who had responded to treatment. Seven donors, including 4 who had experienced a complete response and 3 with partial response to treatment with anti–PD-1 therapy, supplied fecal materials to treat the 16 patients. Each study participant received a single donor–derived FMT followed by additional pembrolizumab therapy every 3 weeks until disease progression or intolerable toxicity. OUTCOME MEASURES
Progression-free survival (PFS) and overall survival (OS). In addition, researchers conducted and compared detailed analyses of fecal biome in patients and donors. They analyzed a total of 223 fecal samples from 15 of the recipients and from 7 donors. KEY FINDINGS
Fifteen of the enrolled patients received FMT and had at least 1 restaging scan via computed tomography (CT) and were evaluable for response. One patient declined so rapidly as their disease progressed that their response was not included. Researchers noted objective responses (ORs) in 3 out of the 15 patients, a 20% response rate. In addition, 3 of the 15 patients, an additional 20%, had durable sustained disease (SD) that lasted longer than 12 months. PFS and OS of all patients were 3.0 and 7.0 months, respectively, at a median follow-up of 7 months. In the 6 patients with disease control (ie, OR and SD), median PFS and OS were both 14.0 months, respectively. Among these patients, 1 patient exhibited ongoing partial response after >2 years and is currently on surveillance, and 4 patients still remain on treatment. One patient who had a complete response to treatment died from a complication of an elective surgery unrelated to their cancer or to treatment. FMT together with pembrolizumab treatment overcame resistance to anti– PD-1 treatment in a subset of refractory melanoma patients. 20 ©2021 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, MAY 2021 SUPPLEMENT—VOL. 13, NO. 51 (SUPPL)
By Jacob Schor, ND, FABNO PRACTICE IMPLICATIONS Note: A similar study by Baruch et al was published in the same issue of Science as this study by Davar et al under discussion. In the Baruch study, 10 patients with refractory metastatic melanoma were treated with FMT from 2 donors who had complete responses to prior immunotherapy treatment. The combination of FMT and, in the Baruch study, nivolumab rather than pembrolizumab resulted in 3 responses, including 1 complete response.1 Both of these drugs, pembrolizumab and nivolumab, are monoclonal antibodies that bind to and block PD-1. The US Food and Drug Administration approved them at about the same time; pembrolizumab was approved in September 2014 and nivolumab that December, for treating advanced melanoma. They are now both approved to treat a range of cancers. PD-1 is a negative regulator of T-cell immune function; that is, it suppresses the immune system’s response. This suppression guards against autoimmune disease, but it also weakens the immune system’s ability to kill cancer cells. Anti–PD-1 drugs, such as these, halt this suppression, allowing the immune system to recognize and kill cancer cells.2 These drugs provide long-term clinical benefit to nearly 40% of patients with advanced melanoma, though only 10% to 20% of patients will have durable complete responses.3 Researchers are directing their efforts toward increasing this response rate. Aware that antibiotic use with these drugs is associated with poorer response rates, and knowing the microbiota influence on the development and function of the immune (continued on page 22)
