Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of Paclitaxel, Carboplatin, and Bevacizumab in Non–small Cell Lung Cancer Patients

Abstract

Purpose: Chemotherapy has long been the standard treatment for advanced stage non-small cell lung cancer (NSCLC), but checkpoint inhibitors are now approved for use in several patient groups and combinations. To design optimal combination strategies, a better understanding of the immunemodulatory capacities of conventional treatments is needed. Therefore, we investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on the immune populations associated with the response to checkpoint inhibitors in peripheral blood.Experimental Design: A total of 223 patients with stage IV NSCLC, enrolled in the NVALT12 study, received PCB, with or without nitroglycerin patch. Peripheral blood was collected at baseline and after the first and second treatment cycle, proportions of T cells, B cells, and monocytes were determined by flow cytometry. Furthermore, several subsets of T cells and the expression of Ki67 and coinhibitory receptors on these subsets were determined.Results: Although proliferation of CD4 T cells remained stable following treatment, proliferation of peripheral blood CD8 T cells was significantly increased, particularly in the effector memory and CD45RA þ effector subsets. The proliferating CD8 T cells more highly expressed programmed death receptor (PD)-1 and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) compared with nonproliferating CD8 T cells. Immunologic responders (iR; >2 fold increased proliferation after treatment) did not show an improved progression-free (PFS) or overall survival (OS).Conclusions: Paclitaxel/carboplatin/bevacizumab induces proliferation of CD8 T cells, consisting of effector cells expressing coinhibitory checkpoint molecules. Induction of proliferation was not correlated to clinical outcome in the current clinical setting. Our findings provide a rationale for combining PCB with checkpoint inhibition in lung cancer.

Platinum Derivatives Effects on Anticancer Immune Response

“…Similar observations were shown in lung cancer patients, with different histological characteristics and treated with cisplatin or carboplatin-derived chemotherapy [120]. In NSCLC patients treated with paclitaxel/carboplatin/bevacizumab, proliferating peripheral blood CD8 + T cells express a higher level of PD-1 and CTLA-4 compared to non-proliferating CD8 + T cells [110]. In vitro, small cell lung cancer (SCLC) cells resistant to cisplatin after continuous exposure to low doses express higher levels of PD-1 and PD-L1, leading to survival and proliferation [121].…”

“…In ovarian cancer patients, carboplatin does not affect CD8 + T-cell proportion in blood, but it increases their capacity to produce IFNγ [109]. In NSCLC patients treated with paclitaxel/carboplatin/bevacizumab, CD8 + T-cell proliferation in peripheral blood is slightly increased [110].…”

“…Breast Cancer anti-PD-1 patient response [116] HNSCC No effect on PD-L1 expression [118] NSCLC PD-L1 expression in patient biopsies [122] Paclitaxel/carboplatin/bevacizumab PD-1 and CTLA-4 on proliferating peripheral CD8 + T-cells [110] Even if platinum derivatives seem to induce PD-1/PD-L1 expression, some discrepancies were observed. This might be explained by the cell lines (more about the genetic background than tumor type) and compound concentrations used, or by a possible indirect effect of platinum derivatives on cancer cells or neighboring cells that will in turn regulate PD-L1 expression.…”

PD‐(L)1 inhibitors vs. chemotherapy vs. their combination in front‐line treatment for NSCLC: An indirect comparison

“…Chemotherapy agents also increase the nuclear factor kappa‐light chain‐enhancer of activated B‐cells and CD8+ T cells, and these cells may work better with the help of PD‐1/L1 inhibitors . A recent study found chemotherapy induces proliferation of CD8 + T cells, consisting of effector cells expressing coinhibitory checkpoint molecules, which would offer an appropriate binding site for immune checkpoint inhibitors . These studies also provided theoretical basis that chemotherapy would change the “desert” immune microenvironment into “inflamed” one .…”

<p>Anti-Angiogenic Therapy in the Treatment of Non-Small Cell Lung Cancer</p>

“…Bevacizumab is a completely humanized mAb which binds to VEGF-A and interferes the interaction between VEGF-A and VEGFR-2. 49 , 50 In 2006, the US Food and Drug Administration (FDA) approved bevacizumab for patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC. 51 The phase III ECOG4599 trial compared the efficacy and safety of carboplatin + paclitaxel with that of carboplatin + paclitaxel + bevacizumab in the patients with recurrent or advanced NSCLC.…”