Exposure to anti‐PD‐1 causes functional differences in tumor‐infiltrating lymphocytes in rare solid tumors

Abstract

The pervasive use of therapeutic antibodies targeting programmed cell death protein 1 (PD-1) to boost anti-tumor immunity has positioned this approach to become the standard-of-care for some solid tumor malignancies. However, little is known as to how blockade of PD-1 may alter the function or phenotype of tumor-infiltrating lymphocytes (TIL). We used our ongoing Phase II clinical trial of pembrolizumab for patients with rare solid tumors from various types (NCT02721732) with matched core biopsies taken at baseline and after initial dose of anti-PD-1 (15-21 days post-dose) to elucidate this question. One fresh core needle biopsy was used to propagate TIL ex vivo to analyze phenotype and function using flow cytometry in both CD8 + and CD4 + TIL populations. An enriched CTLA-4 expression in the CD4 + TIL population was observed in TIL expanded from the on-treatment samples compared to TIL expanded from the matched baseline (n = 22, p = 0.0007) but was not observed in patients who experienced tumor regression. Impact on functionality was evaluated by measuring secretion of 65 soluble factors by expanded TIL from 26 patients at baseline and on-treatment. The CD8 + TIL population demonstrated a diminished cytokine secretion profile post-pembrolizumab. Overall, our study assesses the ramifications of one dose of anti-PD-1 on TIL in rare solid tumor types.Keywords: Anti-PD-1 r CTLA-4 r Immunotherapy r Rare solid tumors r TIL Additional supporting information may be found online in the Supporting Information section at the end of the article.

MDSC subtypes and CD39 expression on CD8+ T cells predict the efficacy of anti‐PD‐1 immunotherapy in patients with advanced NSCLC

“…Recently, immune checkpoint inhibitors of the programmed death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) interaction have emerged as a new therapeutic approach for advanced stages of lung cancer. Three immune checkpoint inhibitors, pembrolizumab, nivolumab, and atezolizumab, are now approved for use in patients with advanced NSCLC [3–6].…”

Serum sCD25 Protein as a Predictor of Lack of Long-Term Benefits from Immunotherapy in Non-Small Cell Lung Cancer: A Pilot Study

“…However, it is probably not derived from the tumor microenvironment. In patients with rare solid tumors, exposure to the anti-PD-1 agent resulted in decreased secretion of sIL-2R in CD8+ tumor-infiltrating lymphocytes [54]. The source of the sCD25 could be the tumor tissue.…”

The current knowledge concerning solid cancer and therapy

“…In ICI approaches, antibodies are designed to suppress the activity of these checkpoint mediators, among them inhibition of PD‐1 has found to represent prolonged OS and progression‐free survival, as well as exhibiting lower toxicities. [ 141–143 ] Table 3 shows the clinical trials carried out recently for targeting solid tumors by immunotherapy.…”

“…[ 154 ] Thus, determining patient responses early in the treatment course is important for early adjustment of the therapy regimen. [ 157 ] Creasy et al [ 141 ] in a study administered a single dose of the anti‐PD‐1 pembrolizumab to patients with rare solid tumors, and they came to the finding that such therapy will result in tumor resistance by enhancing the expression of CTLA‐4 on CD4 + tumor‐infiltrating lymphocyte (TIL) cell surface, and reducing cytokine secretion from CD8 + TILs. Therefore, single‐agent single‐dose therapy not only is ineffective for immune activation but also promotes mechanisms of resistance allowing such tumors to evade from therapy.…”