Combination immune checkpoint blockade as an effective therapy for mesothelioma

Abstract

2018) Combination immune checkpoint blockade as an effective therapy for mesothelioma, OncoImmunology, 7:10, e1494111, ABSTRACT Mesothelioma is an aggressive asbestos induced cancer with extremely poor prognosis and limited treatment options. Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including mesothelioma. However, the efficacy of ICPB and which immune checkpoint combinations constitute the best therapeutic option for mesothelioma have yet to be fully elucidated. Here, we used our well characterised mesothelioma tumour model to investigate the efficacy of different ICBP treatments to generate effective therapy for mesothelioma. We show that tumour resident regulatory T cell co-express high levels of CTLA-4, OX40 and GITR relative to T effector subsets and that these receptors are co-expressed on a large proportion of cells. Targeting any of CTLA-4, OX40 or GITR individually generated effective responses against mesothelioma. Furthermore, the combination of αCTLA-4 and αOX40 was synergistic, with an increase in complete tumour regressions from 20% to 80%. Other combinations did not synergise to enhance treatment outcomes. Finally, an early pattern in T cell response was predictive of response, with activation status and ICP receptor expression profile of T effector cells harvested from tumour and dLN correlating with response to immunotherapy. Taken together, these data demonstrate that combination ICPB can work synergistically to induce strong, durable immunity against mesothelioma in an animal model. ARTICLE HISTORY

The role and therapeutic implications of T cells in cancer of the lung

“…49 Therefore, therapeutically targeting the OX40 axis to stimulate long-term T-cell responses and reduce Treg burden is an attractive target for treatment of lung cancers. 52 Unfortunately, there are limited data on aOX40 therapy in a lung cancer setting, although clinical trials are ongoing for NSCLC (NCT02315066). 50 Clinical trials have validated anti-OX40 efficacy.…”

“…52 In clinical trials, nivolumab and ipilimumab combination therapy achieved an overall response rate of 43% in unselected patients with NSCLC, compared with 23% in the nivolumab monotherapy group; and in the PD-L1 positive subgroup, nivolumab in combination with ipilimumab showed a response rate of 57%, whilst nivolumab alone was 28% (CheckMate 012 study). 52 In clinical trials, nivolumab and ipilimumab combination therapy achieved an overall response rate of 43% in unselected patients with NSCLC, compared with 23% in the nivolumab monotherapy group; and in the PD-L1 positive subgroup, nivolumab in combination with ipilimumab showed a response rate of 57%, whilst nivolumab alone was 28% (CheckMate 012 study).…”

“…Studies from our laboratory have demonstrated combination aOX40 + aCTLA-4 therapy to improve survival and tumor regression in preclinical mesothelioma models. 52 Unfortunately, there are limited data on aOX40 therapy in a lung cancer setting, although clinical trials are ongoing for NSCLC (NCT02315066).…”

“…Promising results with ICPB monotherapy have been followed up by preclinical data suggesting that aPD-1 antibody in combination with aCTLA-4 antibody may increase antitumor activity. 52 In clinical trials, nivolumab and ipilimumab combination therapy achieved an overall response rate of 43% in unselected patients with NSCLC, compared with 23% in the nivolumab monotherapy group; and in the PD-L1 positive subgroup, nivolumab in combination with ipilimumab showed a response rate of 57%, whilst nivolumab alone was 28% (CheckMate 012 study). 53 Further, a phase-II clinical trial investigating dual ipilimumab + nivolumab therapy demonstrated enhanced and durable antitumor responses, with a 30% overall objective response rate in advanced NSCLC patients (n = 252; CheckMate 568).…”

Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome

“…10 In addition, AB1-HA is susceptible to immunotherapy [11][12][13][14] despite not having a high mutation burden, 15,16 as preliminary studies are now suggesting for the human counterpart. 12,17 AB1-HA has two known, tractable tumor antigens, a previously described neo-antigen, UQCRC2 18 and hemagglutinin 19 previously transfected into the cell line as a model neo-antigen. 19 We hypothesized that ICPB would increase the magnitude of these neo-antigen specific T cell responses as well as unmasking responses to additional neo-antigens from in silico predicted candidates.…”