ABSTRACT
BACKGROUND: Combined immune checkpoint inhibitor (ICI) treatment targeting PD-1 and CTLA-4 was suggested to yield clinical benefit over chemotherapy in malignant pleural mesothelioma (MPM), whereas aPD-1 monotherapy failed to provide benefit in phase-III trials. Success of ICI depends on the presence and activation of tumor-specific T cells. Therefore, we investigated whether T-cell characteristics are underlying clinical efficacy of ICI treatment in MPM. METHODS: Comprehensive immune cell profiling was performed on screening and on treatment peripheral blood samples of mesothelioma patients treated with nivolumab (aPD-1) monotherapy (NCT02497508), or a combination of nivolumab and ipilimumab (aCTLA-4) (NCT03048474). FINDINGS: aPD-1/aCTLA-4 combination treatment induced a profound increase in proliferation and activation of T cells, which was not observed upon aPD-1 monotherapy. Moreover, patients that responded to combination treatment had low frequencies of naive CD8 T cells and high frequencies of effector memory CD8 T cells that re-expressed RA (TEMRA) at screening. The frequency of Granzyme-B and Interferon-γ producing TEMRAs was also higher in responding patients. INTERPRETATION: High proportions of TEMRAs and cytokine production by TEMRAs before treatment, was associated with a better clinical outcome. TEMRAs, which likely comprise tumor-specific T cells, tend to require blockage of both aPD-1 and aCTLA-4 to be reactivated. In conclusion, peripheral blood TEMRAs can play a key role in explaining and predicting clinical benefit upon aPD-1/aCTLA-4 combination treatment. FUNDING: Bristol-Myers Squibb sponsored NivoMes and INITIATE clinical trials and provided study drugs. No external funding was applicable for the flow cytometric analyses of peripheral blood samples described in this manuscript.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunologic Memory/drug effects , Mesothelioma, Malignant/drug therapy , Molecular Targeted Therapy , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , CTLA-4 Antigen/antagonists & inhibitors , Clinical Trials as Topic , Female , Humans , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Proteins/metabolism , Ipilimumab/administration & dosage , Male , Mesothelioma, Malignant/etiology , Mesothelioma, Malignant/metabolism , Mesothelioma, Malignant/mortality , Middle Aged , Molecular Targeted Therapy/adverse effects , Molecular Targeted Therapy/methods , Nivolumab/administration & dosage , Prognosis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , T-Lymphocyte Subsets , T-Lymphocytes, Cytotoxic/metabolism , Translational Research, Biomedical , Treatment OutcomeABSTRACT
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 immune-modulatory 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+ 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.
