Immune Activation in Early-Stage Non–Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab

Abstract

Purpose To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early stage non-small cell lung cancer (NSCLC) patients. Experimental Design This is a single-arm chemotherapy plus phased ipilimumab Phase II study of 24 treatment-naïve patients with Stage IB–IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles. Results Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28 dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated TILs than those observed in PBMCs. Surprisingly, we found 4 cases of pre-existing tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating Tregs and MDSCs. Conclusions This study did not meet the primary endpoint of detecting an increase in blood based tumor associated antigen T cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunological data from combined immune checkpoint blockade immunotherapies.

Immunotherapy: From Advanced NSCLC to Early Stages, an Evolving Concept

“…Most of the available studies were performed in advanced/metastatic recurrent NSCLC. Two studies were done in the neoadjuvant setting (25)(26)(27)(28). In a phase I study (25,26), 21 eligible patients with stage IB-IIIA resectable NSCLC received two doses of nivolumab (3 mg/kg) on days 28 and 14 before surgical resection.…”

“…No unexpected adverse event and no operative mortality were observed (26). The primary objective of the phase II study (27,28) was "to assess whether the appearance of T cells activated against select tumor-associated antigens (TAA) increased from baseline following treatment with ipilimumab" and this endpoint was not met. Twenty-four stage IIA-IIIA NSCLC received 3 cycles of induction cisplatin or carboplatin plus paclitaxel with ipilimumab (10 mg/kg) during cycles 2 and 3.…”

“…Pharmacoeconomic analyses from randomized trials.LYG, life year gained; QALY, quality adjusted life years.stage I-III NSCLC showed major pathological responses, despite sometimes a poor clinical response rate after a short period of treatment(25)(26)(27)(28). Other trials are on the way for induction before surgery [Atezolizumab in Stage IB, II, or IIIA (NCT02927301), Durvalumab (NCT03030131), Nivolumab in Stage IB-IIIA (NCT02595944), Pembrolizumab in N2 disease (NCT03053856)]…”

Exosome miR‐27a‐3p secreted from adipocytes targets ICOS to promote antitumor immunity in lung adenocarcinoma

“…Yi et al . have reported that T cells from peripheral blood and tumor tissues of patients treated with anti‐CTLA‐4 for NSCLC had an increased expression of ICOS . ICOS upregulation on T cells is correlated with increased clinical responses induced by CTLA‐4 inhibition .…”

Aerosol Immunotherapy with or without Cisplatin for metastatic lung cancer non-small cell lung cancer disease: In vivo Study. A more efficient combination

“… 15 Ipilimumab is another drug that is currently being investigated for lung cancer treatment in combination with other immunotherapy drugs. 16 Aerosol treatment for systematic diseases has been previously established and is being used for diabetes, chronic obstructive pulmonary disease (COPD), cystic fibrosis and pulmonary hypertension. 17 - 21 Previously we have modified nivolumab, ipilimumab and pembrolizumab to be produced as aerosol.…”