The response to a single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in patients with stage III/IV resectable melanoma, researchers report.
"The most important and interesting point was that a single dose can result in complete eradication of the tumor, and the immune effect can occur extremely rapidly (within 7 days)," Dr. Alexander C. Huang from Perelman School of Medicine, in Philadelphia, told Reuters Health by email.
Immunological responses to checkpoint blockade have been observed as early as three weeks in blood, but the kinetics of immune reinvigoration in the tumor and the relationship to pathological response and clinical outcomes remain unclear.
Dr. Huang and colleagues investigated pathologic and immunologic responses in melanoma tumors removed from 27 patients 17 to 42 days after a single neoadjuvant dose of the anti-PD-1 pembrolizumab and compared these responses with clinical outcomes.
On histologic assessment, eight of 27 patients (29.6%) had a complete (no residual tumor identified) or major (10% or less viable tumor cells) pathologic response; the one-year disease-free survival (DFS) was 63%. The median DFS had not been reached at 25 months' median follow-up.
These rapid responses were associated with accumulation of exhausted CD8 T cells in the tumor at three weeks and with reinvigoration in the blood as early as one week after the single neoadjuvant dose of pembrolizumab, the team reports in Nature Medicine, online February 25.
Transcriptional analysis revealed a strong pretreatment signature, including genes involved in T cell activation, adaptive immune response and T cell migration that correlated with post-treatment tumor-infiltrating lymphocyte (TIL) responses and recurrence-free survival. Post-treatment tumor also revealed a distinct signature of T cell activation, compared with pretreatment.
Recurrence tumor samples from three patients implicated immune suppression, mutational escape and/or tumor evolution as likely mechanisms of resistance.
"These observations support the idea that, even in localized disease, the tumor microenvironment is already primed for response or nonresponse to checkpoint blockade," the researchers conclude. "Future neoadjuvant studies will allow further study of mechanisms of resistance that may help tailor therapies and/or clinical trials in patients."
"The clinical outcomes of PD-1 blockade is largely determined within the first 3 weeks, and it's during this window that resistance mechanisms can be predicted (for example, by pathologic response, TIL infiltration, or Treg activation) and countered (for example, with Treg depletion therapies)," Dr. Huang said.
Dr. Michele W. L. Teng from QIMR Berghofer Medical Research Institute, in Herston, Australia, who has researched various aspects of neoadjuvant cancer immunotherapy, told Reuters Health by email, "Neoadjuvant immunotherapy can identify good and poor responders and allows in-depth study of the mechanisms of adaptive resistance that can develop following immune-checkpoint blockade."
"A key question is whether to give patients neoadjuvant combination immunotherapy rather than just neoadjuvant anti-PD-1, given the higher pathologic complete response (pCR) observed in the former, which likely translates to improved DFS and overall survival," she said. "While the OPACIN trial found increased toxicity using neoadjuvant combination anti-PD-1 plus anti-CTLA4, their recent clinical trial (OPACIN-neo) demonstrated that using a lower dose of anti-CTLA4 with anti-PD-1, they could maintain high pCR with reduced toxicities."
"Currently, it is still unclear what is the optimal treatment and surgery schedule for neoadjuvant treatment of cancers and whether different cancer types will require different scheduling," said Dr. Teng, who was not involved in the new study. "Long-term follow-up studies will be required to determine the optimal treatment and surgery schedule of neoadjuvant immunotherapy for the treatment of patients with stage III resectable melanoma."
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