Deep and Durable Response to Nivolumab and Temozolomide in Small-Cell Lung Cancer Associated With an Early Decrease in Myeloid-Derived Suppressor Cells

Abstract

Background:: Immune checkpoint inhibitors are now an approved treatment for patients with extensive-stage small cell lung cancer (SCLC), an aggressive and incurable malignancy. However, the median survival for patients remains around 1 year, and treatment in the second line and beyond is associated with a low likelihood of response. There currently are no data regarding the optimal treatment of patients who progress on upfront chemo-immunotherapy, and biomarkers are needed to aid patient selection. Obtaining sufficient tissue for advanced molecular testing is a challenge in SCLC due to often limited or crushed tissue specimens. Reliable blood based biomarkers may augment tissue based testing and allow for repeated assessments that is often not possible with tumor tissue, and changes in the peripheral blood may provide information regarding the tumor microenvironment. Myeloid-derived suppressor cells (MDSC) exert immunosuppressive function and have been investigated as a potential barrier to response to immune checkpoint inhibitor (ICI) therapy. Here we demonstrate that MDSC level and function can be readily assessed in the peripheral blood at multiple time points during treatment with combination immunotherapy and temozolomide.

Results:: This report represents the first case of a patient with refractory SCLC treated with combination nivolumab and temozolomide as part of a clinical trial (NCT03728361), who sustained a deep and durable clinical response that was accompanied by an early decrease in MDSC and improved T cell function (increased CD8+ and CD4+ T cell proliferation). We review the literature regarding use of ICI in SCLC and the evidence supporting MDSC as a possible target to enhance the activity of immunotherapy, and emphasize the importance of assessing immune cell subsets as correlative studies in clinical trials.

Conclusion:: An assessment of MDSC level and function during treatment, as well as other immune cell subsets, should be included in prospective studies to further evaluate these assays as possible blood-based biomarkers.

Keywords: Biomarker; Chemotherapy; Immune checkpoint inhibitor; Immunomodulation; Immunotherapy.

Conflict of interest statement

Competing interests: Dr. Owen received an institutional research grant to conduct the clinical trial NCT03728361 from Bristol Myers Squibb (BMS). Nivolumab was provided by BMS. Dr. Verschraegen and Dr. Otterson have received institutional research grants from BMS. The study was designed and the data reported here was generated solely by the OSU investigator team.

Figures

Figure 1.. Baseline and response to first line treatment.

Computed tomography images of chest, abdomen and pelvis at the time of diagnosis (Figures 1A and 1C) and after 2 cycles of first-line treatment with standard of care chemotherapy showing response in lung (indicated by asterisk) and liver lesions (Figures 1B and 1D).

Figure 2.. Clinical response to nivolumab and temozolomide is accompanied by decreased total MDSC and increased T cell proliferation.

A-C: Representative images showing complete resolution of a left lower lobe lung mass (*) after 8 weeks of study therapy with ICI and chemotherapy (B) that was sustained at 24 weeks (C). Circulating levels of total MDSC (CD11b+, CD33+, HLA-DRlo/−), monocytic (M-MDSC; CD14+) and granulocytic (PMN-MDSC; CD66b+) MDSC were measured by CyTOF at screening and at cycle 1, day 15 of nivolumab and temozolomide treatment and summarized in (D). Patient PBMCs were labeled with carboxyfluorescein succinimidyl ester (CFSE) and activated with anti-CD3/CD28 beads. Following 72 hours, cells were collected and stained with anti-CD8 (PE-Cy7) and anti-CD4 (APC) antibodies and proliferation was assessed by flow cytometry. Histograms and bar graphs of fold change quantification between screening and cycle 1, day 15 (C1D15) are shown for (E) CD8+ T cell proliferation and (F) CD4+ T cell proliferation.