Immune checkpoint inhibitors have changed the treatment landscape of certain cancer types, and a recent study aims to provide new insight on why treatment response varies so much from patient to patient.
Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer care in recent years, showing impressive efficacy and less toxicity than chemotherapy in some settings. But they have only been successful in certain tumor types thus far. A recent study aimed to shed light on potential mechanisms behind varied tumor responses to ICIs targeting programmed cell death protein 1 (PD-1).
Anti–PD-1 ICIs are approved by the FDA for use on any solid tumors with deficient DNA mismatch repair (MMR), elevated microsatellite instability (MSI), or high tumor mutational burden (TMB). PD-1 inhibition is also approved in combination with chemotherapy or without it in the first line for lung cancer, head and neck cancer, kidney cancer, and cutaneous melanoma.
Anti–PD-1 therapy mainly kills tumor cells by stimulating cytotoxic CD8+ T cells. The aforementioned types of tumors are presumed more likely to respond to ICIs due to a “hot” tumor microenvironment (TME) with a high neoantigen load for immune stimulation and high levels of tumor-infiltrating lymphocytes (TILs).
Tumor types that do not generally respond to PD-1 inhibitors, on the other hand, presumably have “cold” TMEs with low TMB and little TIL penetration. Still others are considered “warm,” with a significant number of patients who do not have MMR deficiency, high MSI, or high TMB still responding to anti–PD-1 therapies.
At least one previous study has also shown that established predictive biomarkers of response, PD-L1 expression in tumor cells and immune cells, were not significantly associated with clinical response to anti–PD-1 therapy with pembrolizumab in patients with advanced small bowel adenocarcinoma (SBA).
The current study aimed to clarify some of the mechanisms behind anti–PD-1 response by doing peripheral blood-based analyses concurrently with a phase 2 clinical trial of pembrolizumab involving 40 patients with SBA. Blood-based analysis allows easier serial testing and monitoring of patient responses versus tissue-based immunohistochemistry and DNA sequencing, which only offer an isolated picture of the TME and require tissue sampling. For blood-based analyses, circulating biomarkers such as peripheral T cell subsets and circulating tumor DNA are potential indicators of response potential and overall prognosis.
Of the 40 patients, 35 had blood samples collected. Three of these patients had confirmed partial response (PR), 9 showed stable disease, 22 experienced disease progression, and 1 could not be evaluated. Only the 3 who achieved partial response were considered responders. A further exploratory study using a novel, ex vivo cytotoxicity assay was done on 12 additional patients with advanced pancreatic adenocarcinoma (PDAC) and colorectal adenocarcinoma (CRA).
Lower baseline levels of Bim, a proapoptotic molecule that triggers apoptosis in B cell lymphoma-2 molecules, in circulating CD8+ T cells was linked to clinical benefit from anti–PD-1 therapy. Radiographic response and better progression-free survival (PFS) were seen with lower baseline Bim+/CD11ahi CD8+ T cells in SBA.
Lower levels of NKG7 at baseline were also associated with better treatment response in SBA. Past research has also shown NKG7 to be important in facilitating cytotoxic functions of effector T cells. While lower levels at baseline showed an association with anti–PD-1 response, higher levels after therapy initiation were associated with longer PFS and disease control.
Upregulation of CX3CR1 in peripheral blood samples was associated with longer overall survival in the current study.
The exploratory cytotoxic assay of patient-derived peripheral blood mononuclear cells (PBMCs) showed higher antitumor toxicity in CRA compared with PDAC regardless of anti–PD-1 exposure, which aligns with current knowledge. Patients whose PBMCs whose disease was controlled showed higher PBMC-mediated cytotoxicity post-treatment than those whose disease progressed. However, this biomarker may not serve predictive purposes at baseline, when there were no notable differences in responders versus non-responders.
Overall, the findings suggest that Bim and NKG7 may be useful markers, with NKG7 potentially holding predictive and prognostic value for anti–PD-1 therapy. CX3CR1 could also be a marker for durable clinical benefit, given the consistent association between them in this study.
“Overall, these findings suggest that the frequency and cytolytic capacity of circulating, effector immune cells may differentiate clinical response to ICIs,” the authors wrote, “providing a strong rationale to support immune monitoring using patient peripheral blood.”
Evaluating the ex vivo cytotoxicity assay for potential use as a clinical tool to gauge disease progression will also be crucial, given radiographic imaging may not accurately assess atypical responses to ICI therapy.
Zhu M, Zhang H, Pedersen KS, et al. Understanding suboptimal response to immune checkpoint inhibitors. Adv Biol (Weinh). Published online March 27, 2022. doi:10.1002/adbi.202101319