Human Immune Responses to Tumor Antigens for Cancer Immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

[] IMMUNE CORRELATES WITH RESPONSE IN PATIENTS WITH METASTATIC SOLID TUMORS TREATED WITH A TUMOR TARGETING IMMUNOCYTOKINE NHS-IL12. Interleukin 12 (IL-12) is a pro-inflammatory cytokine produced by activated dendritic cells, macrophages, and neutrophils and acts mainly on natural killer (NK) cells, natural killer T(NKT) cells, and CD8+ T cells to enhance proliferation and cytotoxicity. IL-12 drives CD4+ T cells towards a T helper 1 (Th1) phenotype and leads to interferon (IFN) gamma production by T and NK cells, thus promoting cell-mediated immunity. In addition, IL-12 can alter the function of immunosuppressive cells in the tumor microenvironment (TME) by inhibiting and reprogramming tumor-associated macrophages and myeloid-derived suppressor cells to enhance pro-inflammatory function, antigen presentation and support of T-cell responses. IL-12 treatment in preclinical mouse models, alone or in combination with other therapies, yielded promising results with significant antitumor activity and improved survival; however, recombinant human IL-12 (rhIL-12) in clinical studies resulted in serious adverse effects. NHS-IL12 is an immunocytokine fusion protein composed of two molecules of IL-12 fused to each of the heavy-chains of the human IgG1 NHS76 antibody. NHS76 targets DNA/histones exposed in necrotic areas of solid tumors, thus delivering IL-12 to the TME, sparing systemic accumulation. Preclinical studies using a murine version of the immunocytokine, designated NHS-muIL12, resulted in lower levels of serum IFNgamma induction, greater accumulation in tumors, and greater antitumor effects compared to recombinant murine IL-12. The first-in-human clinical trial administered NHS-IL12 subcutaneously in 59 patients treated every 4 weeks (Q4W), with a maximum tolerated dose of 16.8 mcg/kg. The phase I study was expanded to include a high-exposure cohort that received bi-weekly treatment (Q2W) with two dose levels of NHS-IL12: 12.0 mcg/kg and 16.8 mcg/kg. Patients given NHS-IL12 were analyzed both prior to and early after treatment for effects on 10 serum soluble analytes, complete blood counts, and 158 peripheral immune subsets. Higher levels of immune activation were seen with a dose of 16.8 mcg/kg versus 12.0 mcg/kg in patients in the high-exposure cohort, as evidenced by greater increases in serum IFNgamma, TNFalpha, and soluble PD-1, and greater increases in frequencies of peripheral ki67+ mature NK, CD8+T, and NKT cells. Greater immune activation was also seen in the Q2W versus Q4W cohort, as demonstrated by greater increases in pro-inflammatory serum analytes, ki67+ CD8+ T, NK, and NKT cells, intermediate monocytes, and a greater decrease in CD73+ T cells. Specific immune analytes at baseline including lower levels of monocytes and plasmacytoid dendritic cells, and early changes after treatment such as an increase in refined NK cell subsets and total CD8+ T cells, associated with better clinical response. These findings may help to guide future schedule and dosing regimens of clinical studies of NHS-IL12 as monotherapy and in combination therapies. [] IMMUNE CORRELATES OF CLINICAL PARAMETERS IN PATIENTS WITH HPV-ASSOCIATED MALIGNANCIES TREATED WITH BINTRAFUSP ALFA. Tumor biopsies of metastatic lesions of patients with most solid tumors, such as those with human papillomavirus (HPV)-associated malignancies, are often not available or difficult to obtain, and define only one point in time in the evolution of a tumor mass or masses. This study was undertaken to determine if analysis of the peripheral immunome would aid in determining which patients with HPV-associated malignancies would most likely benefit clinically from treatment with the novel immunotherapeutic agent anti-PDL1/TGFbetaRII, bintrafusp alfa. The results of the study demonstrate that interrogation of both cellular and soluble components of the peripheral immunome, either prior to therapy, or early in the therapeutic regimen, can help define which patients are most likely to benefit clinically. This study also provides further evidence to the field that, in addition to analysis of tumor biopsies, interrogation of the peripheral immunome can aid in defining the mechanism of action of a given immunotherapeutic and potentially provide valuable prognostic information. Bintrafusp alfa is a bifunctional agent consisting of an anti-human PD-L1 antibody linked to two TGFbetaRII. It is designed to act both as a checkpoint inhibitor and to 'trap' TGFbeta in the tumor microenvironment. Phase I and II clinical studies demonstrated clinical activity in patients with a range of human papillomavirus (HPV)-associated cancers. The purpose of the studies reported here was the interrogation of various aspects of the peripheral immunome in patients with HPV-associated cancers, both prior to and early in the treatment regimen of bintrafusp alfa to better understand the mode of action of the agent and to help define which patients are more likely to benefit from bintrafusp alfa treatment. The peripheral immunome of patients (n=65) with HPV+ malignancies was analyzed both prior to treatment with bintrafusp alfa and day 14 post-treatment for levels and changes in (1) 158 different immune cell subsets, (2) multiple plasma soluble factors including analytes reflecting immune stimulatory and inhibitory status, (3) complete blood counts, and in a subset of patients (4) TCR diversity and (5) HPV-specific T-cell responses. Interrogation of the peripheral immunome prior to bintrafusp alfa treatment revealed several factors that associated with clinical response, including (1) higher levels of sCD27:sCD40L ratios, (2) lower levels of TGFbeta1 and 12 additional factors associated with tumor mesenchymalization, and (3) higher CD8+ T cell:MDSC ratios. Analysis at 2 weeks post bintrafusp alfa revealed that eventual clinical responders had fewer increases in IL-8 levels and the neutrophil to lymphocyte ratio, and higher levels of HPV-16 specific CD8+ T cells. This study also provided information concerning differences in the peripheral immunome for patients who were naive versus refractory to prior checkpoint inhibition therapy. While preliminary, two multivariate models developed predicted clinical benefit with 76%-91% accuracy. These studies add insight into the mechanism of action of bintrafusp alfa and provide evidence that the interrogation of both cellular and soluble components of the peripheral immunome of patients with HPV-associated malignancies, either prior to or early in the therapeutic regimen, can provide information as to which patients are more likely to benefit with bintrafusp alfa therapy. The peripheral immunome, prior to therapy and during therapy, was also evaluated in the following clinical studies: [] Phase 1 trial of CV301 in combination with anti-PD-1 therapy in non-squamous non-small cell lung cancer. [] A randomized phase II trial of mFOLFOX6 + bevacizumab alone or with AdCEA vaccine + avelumab immunotherapy for untreated metastatic colorectal cancer. [] Joint-predominant rheumatic complications of immune checkpoint inhibitor therapy in patients with thymic epithelial tumors. [] A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1). [] Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer. [] Flutamide with or without PROSTVAC in non-metastatic castration resistant (MO) prostate cancer. [] Avelumab in men with metastatic castration-resistant prostate cancer, enriched for patients treated previously with a therapeutic cancer vaccine. [] Phase 1 trial of CV301 in combination with anti-PD-1 therapy in non-squamous non-small cell lung cancer.