ABSTRACT
A patient with progressive metastatic pancreatic cancer was treated with a single infusion of 16.2×109 autologous T cells that had been genetically engineered to clonally express two allogeneic HLA-C*08:02-restricted T-cell receptors (TCRs) targeting mutant KRAS G12D expressed by the tumors. The patient had regression of visceral metastases (overall partial response of 72% according to the Response Evaluation Criteria in Solid Tumors, version 1.1); the response was ongoing at 6 months. The engineered T cells constituted more than 2% of all the circulating peripheral-blood T cells 6 months after the cell transfer. In this patient, TCR gene therapy targeting the KRAS G12D driver mutation mediated the objective regression of metastatic pancreatic cancer. (Funded by the Providence Portland Medical Foundation.).
Subject(s)
Genetic Therapy , Pancreatic Neoplasms , Proto-Oncogene Proteins p21(ras) , Receptors, Antigen, T-Cell , Genes, T-Cell Receptor/genetics , Genetic Therapy/methods , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Proto-Oncogene Proteins p21(ras)/genetics , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/therapeutic use , Pancreatic NeoplasmsABSTRACT
Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). Combinations of these checkpoint therapies with other agents are now being explored to improve outcomes and enhance benefit-risk profiles of treatment. Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have several potential target oncogenes for molecularly targeted therapy, such as tyrosine kinase inhibitors. Unfortunately, many patients still progress and acquire resistance to immunotherapy and molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been shown to improve prognosis compared to monotherapy. The number of new combinations treatment under development for melanoma provides options for the number of patients to achieve a therapeutic benefit. Many diagnostic and prognostic assays have begun to show clinical applicability providing additional tools to optimize and individualize treatments. However, the question on the optimal algorithm of first- and later-line therapies and the search for biomarkers to guide these decisions are still under investigation. This year, the Melanoma Bridge Congress (Dec 1st-3rd, 2022, Naples, Italy) addressed the latest advances in melanoma research, focusing on themes of paramount importance for melanoma prevention, diagnosis and treatment. This included sessions dedicated to systems biology on immunotherapy, immunogenicity and gene expression profiling, biomarkers, and combination treatment strategies.
Subject(s)
Melanoma , Humans , Melanoma/therapy , Melanoma/drug therapy , Immunotherapy , CTLA-4 Antigen , ItalyABSTRACT
BACKGROUND: The authors hypothesized that patients developing immune-related adverse events (irAEs) while receiving immune checkpoint inhibition (ICI) for recurrent/metastatic head and neck cancer (HNC) would have improved oncologic outcomes. METHODS: Patients with recurrent/metastatic HNC received ICI at 2 centers. Univariate and multivariate logistic regression, Kaplan-Meier methods, and Cox proportional hazards regression were used to associate the irAE status with the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in cohort 1 (n = 108). These outcomes were also analyzed in an independent cohort of patients receiving ICI (cohort 2; 47 evaluable for irAEs). RESULTS: The median follow-up was 8.4 months for patients treated in cohort 1. Sixty irAEs occurred in 49 of 108 patients with 5 grade 3 or higher irAEs (10.2%). ORR was higher for irAE+ patients (30.6%) in comparison with irAE- patients (12.3%; P = .02). The median PFS was 6.9 months for irAE+ patients and 2.1 months for irAE- patients (P = .0004), and the median OS was 12.5 and 6.8 months, respectively (P = .007). Experiencing 1 or more irAEs remained associated with ORR (P = .03), PFS (P = .003), and OS (P = .004) in multivariate analyses. The association between development of irAEs and prolonged OS persisted in a 22-week landmark analysis (P = .049). The association between development of irAEs and favorable outcomes was verified in cohort 2. CONCLUSIONS: The development of irAEs was strongly associated with an ICI benefit, including overall response, PFS, and OS, in 2 separate cohorts of patients with recurrent/metastatic HNC.
Subject(s)
Head and Neck Neoplasms , Immune Checkpoint Inhibitors , Head and Neck Neoplasms/drug therapy , Humans , Immune Checkpoint Inhibitors/adverse effects , Neoplasm Recurrence, Local , Progression-Free Survival , Retrospective StudiesABSTRACT
BACKGROUND/OBJECTIVE: National guidelines do not recommend the routine use of antimicrobial prophylaxis in patients with solid tumors, yet prophylactic agents are still sometimes prescribed for head and neck cancer patients. The purpose of this study is to determine the effect of prophylactic antimicrobials on the incidence of infection in patients undergoing chemoradiation for head and neck cancer. METHODS: Between 2013 and 2016, patients receiving chemoradiation for head and neck cancer at three outpatient oncology clinics were identified by retrospective review. Cohorts were based on administration or absence of prophylactic antimicrobials. The primary outcome of this study was incidence of infection. Secondary outcomes included incidence of hospitalization and length of hospital stay. RESULTS: Seventy-seven patients were analyzed, 47% (n = 36) were not prescribed antimicrobial prophylaxis and 53% (n = 41) were prescribed prophylaxis. Infection occurred in 31 patients in the no prophylaxis cohort and in 34 patients in the prophylaxis cohort (86.1% vs. 82.9%, p = 0.945). Twenty patients in the no prophylaxis cohort were hospitalized versus 16 patients in the prophylaxis cohort (p = 0.222). The average length of hospital stay was 6 days in the no prophylaxis cohort and 10.6 days in the prophylaxis cohort (p = 0.007). CONCLUSION: The use of antimicrobial prophylaxis did not significantly impact the incidence of infection when compared to patients who were not prescribed prophylaxis. There was no difference in the incidence of hospitalization, however, the patients in the prescribed prophylactic group had longer length of hospital stay.
Subject(s)
Anti-Infective Agents/therapeutic use , Chemoradiotherapy/methods , Head and Neck Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Hospitalization , Humans , Incidence , Length of Stay , Male , Middle Aged , Retrospective StudiesABSTRACT
Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies.
Subject(s)
Neoplasms , T-Lymphocytes, Regulatory , Humans , Animals , Mice , Ipilimumab/pharmacology , Ipilimumab/therapeutic use , CTLA-4 Antigen , Tumor Microenvironment , Neoplasms/drug therapyABSTRACT
Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR-NK cell efficacy. Claudin-6 (CLDN6) has been reported to be overexpressed in ovarian cancer and may be an attractive target for CAR-NK cells immunotherapy. However, the feasibility of using anti-CLDN6 CAR-NK cells to treat ovarian cancer remains to be explored. Methods: CLDN6 expression in primary human ovarian cancer, normal tissues and cell lines were detected by immunohistochemistry and western blot. Two types of third-generation CAR NK-92MI cells targeting CLDN6, CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) and CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB) were constructed by lentivirus transfection, sorted by flow cytometry and verified by western blot and qPCR. OVCAR-3, SK-OV-3, A2780, Hey and PC-3 cells expressing the GFP and luciferase genes were transduced. Subcutaneous and intraperitoneal tumor models were established via NSG mice. The ability of CLDN6-CAR NK cells to kill CLDN6-positive ovarian cancer cells were evaluated in vitro and in vivo by live cell imaging and bioluminescence imaging. Results: Both CLDN6-CAR1 and CLDN6-CAR2 NK-92MI cells could specifically killed CLDN6-positive ovarian cancer cells (OVCAR-3, SK-OV-3, A2780 and Hey), rather than CLDN6 negative cell (PC-3), in vitro. CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) exhibited stronger cytotoxicity than CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB). Furthermore, CLDN6-CAR1 NK cells could effectively eliminate ovarian cancer cells in subcutaneous and intraperitoneal tumor models. More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti-PD-L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. Conclusions: These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.
Subject(s)
Claudins , Ovarian Neoplasms , Receptors, Chimeric Antigen , Humans , Animals , Mice , Female , Receptors, Chimeric Antigen/genetics , Ovarian Neoplasms/therapy , Ovarian Neoplasms/metabolism , Cell Line, Tumor , Apoptosis , NK Cell Lectin-Like Receptor Subfamily K/metabolism , CD28 Antigens/metabolism , Killer Cells, Natural , Immunotherapy/methods , Immunotherapy, Adoptive/methodsABSTRACT
The aberrant DNA methylation of tumor suppressor genes occurs frequently in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) and likely affects the initiation and progression of BE to EAC. In the present study, we discovered PKP1 as a novel methylated gene in EAC and then investigated the role of loss of PKP1, a constituent of the desmosome complex found in stratified epithelial layers, on the behavior of Barrett's esophagus and esophageal adenocarcinoma cells. By using primary esophageal tissue samples we determined that PKP1 was rarely methylated in normal squamous esophagus (5/55; 9.1%) and BE (5/39; 12.8%) and more frequently methylated in Barrett's esophagus with high-grade dysplasia (HGD) or EAC (20/60; 33.3%; P < 0.05). Furthermore, PKP1 levels were decreased in BE and HGD/EAC cases compared to normal squamous esophagus cases. Knockdown of PKP1 in the BE cell lines CP-A and CP-D (both normally express PKP1) resulted in increased cell motility. Thus, PKP1 loss secondary to promoter methylation, as well as other mechanisms, may promote the progression of BE to EAC in a subset of patients via decreased desmosome assembly and increased cell motility.
Subject(s)
Adenocarcinoma/genetics , Barrett Esophagus/genetics , DNA Methylation , Esophageal Neoplasms/genetics , Plakophilins/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Barrett Esophagus/metabolism , Barrett Esophagus/pathology , Biomarkers, Tumor/genetics , Cell Movement , Desmosomes/metabolism , Disease Progression , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Humans , Plakophilins/metabolism , Promoter Regions, Genetic , RNA Interference , RNA, Messenger/genetics , RNA, Small Interfering , Tumor Cells, CulturedABSTRACT
There is a critical need to identify molecular markers that can reliably aid in stratifying esophageal adenocarcinoma (EAC) risk in patients with Barrett's esophagus. MicroRNAs (miRNA/miR) are one such class of biomolecules. In the present cross-sectional study, we characterized miRNA alterations in progressive stages of neoplastic development, i.e., metaplasia-dysplasia-adenocarcinoma, with an aim to identify candidate miRNAs potentially associated with progression. Using next generation sequencing (NGS) as an agnostic discovery platform, followed by quantitative real-time PCR (qPCR) validation in a total of 20 EACs, we identified 26 miRNAs that are highly and frequently deregulated in EACs (≥ 4-fold in >50% of cases) when compared to paired normal esophageal squamous (nSQ) tissue. We then assessed the 26 EAC-derived miRNAs in laser microdissected biopsy pairs of Barrett's metaplasia (BM)/nSQ (n = 15), and high-grade dysplasia (HGD)/nSQ (n = 14) by qPCR, to map the timing of deregulation during progression from BM to HGD and to EAC. We found that 23 of the 26 candidate miRNAs were deregulated at the earliest step, BM, and therefore noninformative as molecular markers of progression. Two miRNAs, miR-31 and -31*, however, showed frequent downregulation only in HGD and EAC cases suggesting association with transition from BM to HGD. A third miRNA, miR-375, showed marked downregulation exclusively in EACs and in none of the BM or HGD lesions, suggesting its association with progression to invasive carcinoma. Taken together, we propose miR-31 and -375 as novel candidate microRNAs specifically associated with early- and late-stage malignant progression, respectively, in Barrett's esophagus.
Subject(s)
Barrett Esophagus/genetics , Barrett Esophagus/pathology , Cell Transformation, Neoplastic/genetics , MicroRNAs/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Disease Progression , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Male , Metaplasia/genetics , Middle Aged , Prognosis , Young AdultABSTRACT
The authors of a recent study identified noncanonical peptides (NCP) presented by cancer cells' HLA and observed lack of reactivity to these antigens by endogenous tumor-reactive T cells. In vitro sensitization generated NCP-reactive T cells that recognized epitopes shared by a majority of cancers tested, providing opportunities for novel therapies to shared antigens. See related article by Lozano-Rabella et al., p. 2250.
Subject(s)
Melanoma , Proteogenomics , Humans , Antigens, Neoplasm/immunology , Melanoma/immunology , Ligands , Lighting , PeptidesABSTRACT
Despite pre-clinical murine data supporting T regulatory (Treg) cell depletion as a major mechanism by which anti-CTLA-4 antibodies function in vivo, the two main antibodies tested in patients (ipilimumab and tremelimumab) have failed to demonstrate similar effects. We report analogous findings in an immunocompetent murine model humanized for CTLA-4 and Fcy receptors (hCTLA-4/hFcyR mice), where both ipilimumab and tremelimumab fail to show appreciable Treg depletion. Immune profiling of the tumor microenvironment (TME) in both mice and human samples revealed upregulation of the inhibitory Fcy receptor, FcyRIIB, which limits the ability of the antibody Fc fragment of human anti-CTLA-4 antibodies to induce effective antibody dependent cellular cytotoxicty/phagocytosis (ADCC/ADCP). Blocking FcyRIIB in humanized mice rescues Treg depleting capacity and anti-tumor activity of ipilimumab. For another target, CC motif chemokine receptor 8 (CCR8), which is selectively expressed on tumor infiltrating Tregs, we show that Fc engineering to enhance binding to activating Fc receptors, while limiting binding to the inhibitory Fc receptor, leads to consistent Treg depletion and single-agent activity across multiple tumor models, including B16, MC38 and MB49. These data reveal the importance of reducing engagement to the inhibitory Fc receptor to optimize Treg depletion by TME targeting antibodies. Our results define the inhibitory FcyRIIB receptor as a novel immune checkpoint limiting antibody-mediated Treg depletion in tumors, and demonstrate Fc variant engineering as a means to overcome this limitation and augment efficacy for a repertoire of antibodies currently in use or under clinical evaluation in oncology.
ABSTRACT
BACKGROUND: Preclinically, interleukin-15 (IL-15) monotherapy promotes antitumor immune responses, which are enhanced when IL-15 is used in combination with immune checkpoint inhibitors (ICIs). This first-in-human study investigated NIZ985, a recombinant heterodimer comprising physiologically active IL-15 and IL-15 receptor α, as monotherapy and in combination with spartalizumab, an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody, in patients with advanced solid tumors. METHODS: This phase I/Ib study had two dose-escalation arms: single-agent NIZ985 administered subcutaneously thrice weekly (TIW, 2 weeks on/2 weeks off) or once weekly (QW, 3 weeks on/1 week off), and NIZ985 TIW or QW administered subcutaneously plus spartalizumab (400 mg intravenously every 4 weeks (Q4W)). The dose-expansion phase investigated NIZ985 1 µg/kg TIW/spartalizumab 400 mg Q4W in patients with anti-PD-1-sensitive or anti-PD-1-resistant tumor types stratified according to approved indications. The primary objectives were the safety, tolerability, and the maximum tolerated doses (MTDs) and/or recommended dose for expansion (RDE) of NIZ985 for the dose-expansion phase. RESULTS: As of February 17, 2020, 83 patients (median age: 63 years; range: 28-85) were treated in dose escalation (N=47; single-agent NIZ985: n=27; NIZ985/spartalizumab n=20) and dose expansion (N=36). No dose-limiting toxicities occurred nor was the MTD identified. The most common treatment-related adverse event (TRAE) was injection site reaction (primarily grades 1-2; single-agent NIZ985: 85% (23/27)); NIZ985/spartalizumab: 89% [50/56]). The most common grade 3-4 TRAE was decreased lymphocyte count (single-agent NIZ985: 7% [2/27]; NIZ985/spartalizumab: 5% [3/56]). The best overall response was stable disease in the single-agent arm (30% (8/27)) and partial response in the NIZ985/spartalizumab arm (5% [3/56]; melanoma, pancreatic cancer, gastric cancer). In dose expansion, the disease control rate was 45% (5/11) in the anti-PD-1-sensitive and 20% (5/25) in the anti-PD-1-resistant tumor type cohorts. Pharmacokinetic parameters were similar across arms. The transient increase in CD8+ T cell and natural killer cell proliferation and induction of several cytokines occurred in response to the single-agent and combination treatments. CONCLUSIONS: NIZ985 was well tolerated in the single-agent and NIZ985/spartalizumab regimens. The RDE was established at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs. TRIAL REGISTRATION NUMBER: NCT02452268.
Subject(s)
Antineoplastic Agents , Melanoma , Neoplasms, Second Primary , Humans , Middle Aged , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Interleukin-15/therapeutic use , Melanoma/drug therapy , Neoplasms, Second Primary/drug therapy , Adult , Aged , Aged, 80 and overABSTRACT
PURPOSE: Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown. METHODS AND MATERIALS: We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms. RESULTS: Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol. CONCLUSIONS: Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593).
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Mucositis , Humans , Squamous Cell Carcinoma of Head and Neck/drug therapy , Nivolumab/therapeutic use , Cisplatin/therapeutic use , Carcinoma, Squamous Cell/pathology , Neoplasm Recurrence, Local/pathology , Head and Neck Neoplasms/drug therapy , Fatigue/drug therapyABSTRACT
The clinical response to cancer therapies involves the complex interplay between the systemic, tumoral, and stromal immune response as well as the direct impact of treatments on cancer cells. Each individual's immunological and cancer histories are different, and their carcinogen exposures may differ. This means that even though two patients with oral tumors may carry an identical mutation in TP53, they are likely to have different pre-existing immune responses to their tumors. These differences may arise due to their distinct accessory mutations, genetic backgrounds, and may relate to clinical factors including previous chemotherapy exposure and concurrent medical comorbidities. In isolation, their cancer cells may respond similarly to cancer therapy, but due to their baseline variability in pre-existing immune responses, patients can have different responses to identical therapies. In this review we discuss how the immune environment of tumors develops, the critical immune cell populations in advanced cancers, and how immune interventions can manipulate the immune environment of patients with pre-malignancies or advanced cancers to improve therapeutic outcomes.
ABSTRACT
PURPOSE: The aim of the study was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-CCR4 monoclonal antibody targeting effector regulatory T cells (Treg) in combination with the checkpoint inhibitor nivolumab in patients with locally advanced or metastatic solid tumors. PATIENTS AND METHODS: This was a multicenter, dose-finding (phase I), and dose expansion (phase II) study (NCT02705105) in patients with locally advanced or metastatic solid tumors. There were no dose-limiting toxicities in phase I with mogamulizumab 1 mg/kg every week for cycle 1 followed by 1 mg/kg every 2 weeks plus nivolumab 240 mg every 2 weeks intravenously, and cohort expansion occurred at this dose level. RESULTS: All 114 patients treated with mogamulizumab 1 mg/kg plus nivolumab 240 mg in phases I (n = 4) and II (n = 110) were assessed for safety and efficacy. Mogamulizumab plus nivolumab showed acceptable safety and tolerability. Objective response rate was 10.5% [95% confidence interval (CI), 5.6-17.7; 3 complete and 9 partial responses]. Disease control rate was 36.8%. Median duration of response was 14.4 months. Median progression-free survival was 2.6 (95% CI, 2.3-3.1) months, and median overall survival was 9.5 (95% CI, 5.9-13.5) months. CONCLUSIONS: Combination of mogamulizumab with nivolumab for treatment of patients with locally advanced or metastatic solid tumors did not result in enhanced efficacy. Tolerability of mogamulizumab 1 mg/kg plus nivolumab 240 mg was acceptable.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immune Checkpoint Inhibitors/administration & dosage , Neoplasms/drug therapy , Neoplasms/pathology , Nivolumab/administration & dosage , Adult , Aged , Aged, 80 and over , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Progression-Free Survival , Safety , Treatment OutcomeABSTRACT
PD-L1 testing guides therapeutic decision-making for head and neck squamous cell carcinoma (HNSCC). We sought to understand whether chemoradiation therapy (CRT) influences the PD-L1 combined positive score (CPS) and other biomarkers of response to immunotherapy. PD-L1 expression was assessed using immunohistochemistry, and bulk RNA sequencing was performed on 146 HNSCC patients (65 primary sites, 50 paired local recurrences, and 31 paired regional recurrences). PD-L1 was scored using the CPS of ≥1, ≥20, and ≥50. Overall, 98 %, 54 %, and 17 % of HNSCCs had a CPS ≥1, ≥20, and ≥50, respectively. When using a cut-off of ≥1, CRT did not significantly change CPS at the locoregional recurrent site. However, there were significant changes when using CPS ≥20 or ≥50. The CPS changed for 32 % of patients when using a CPS ≥20 (p < 0.001). When using a CPS ≥50, there was a 20-23 % (p = 0.0058-0.00067) discordance rate at the site of locoregional recurrence. Oral cavity cancers had a significantly higher discordant rate than other primary sites for CPS ≥50, 44 % (8/18, p = 0.0058) and 58 % (7/12, p = 0.00067) discordance at the site of local and regional recurrence, respectively. When evaluating the 18 gene IFN-É£ signature predictive of response to anti-PD-1 blockade, there was a statistically significant increase in the IFN-É£ signature in recurrent larynx cancer (p = 0.02). Our study demonstrates that when using a higher cut-off of CPS ≥20 and ≥50, a repeat biopsy may be warranted after CRT for local and regional recurrent HNSCCs.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Humans , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Squamous Cell Carcinoma of Head and Neck/therapy , Neoplasm Recurrence, Local/metabolism , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/therapy , Carcinoma, Squamous Cell/drug therapyABSTRACT
Patients exhibit distinct responses to immunotherapies that are thought to be linked to their tumor immune environment. However, wide variations in outcomes are also observed in patients with matched baseline tumor environments, indicating that the biological response to treatment is not currently predictable using a snapshot analysis. To investigate the relationship between the immune environment of tumors and the biological response to immunotherapies, we characterized four murine head and neck squamous cell carcinoma (HNSCC) models on two genetic backgrounds. Using tumor explants from those models, we identified correlations between the composition of infiltrating immune cells and baseline cytokine profiles prior to treatment. Following treatment with PD-1 blockade, CTLA-4 blockade, or OX40 stimulation, we observed inter-individual variability in the response to therapy between genetically identical animals bearing the same tumor. These distinct biological responses to treatment were not linked to the initial tumor immune environment, meaning that outcome would not be predictable from a baseline analysis of the tumor infiltrates. We similarly performed the explant assay on patient HNSCC tumors and found significant variability between the baseline environment of the tumors and their response to therapy. We propose that tumor explants provide a rapid biological assay to assess response to candidate immunotherapies that may allow matching therapies to individual patient tumors. Further development of explant approaches may allow screening and monitoring of treatment responses in HNSCC.
ABSTRACT
Surgical resection of head and neck squamous-cell carcinoma (HNSCC) is associated with high rates of local and distant recurrence, partially mitigated by adjuvant therapy. A pre-existing immune response in the patient's tumor is associated with better outcomes following treatment with conventional therapies, but improved options are needed for patients with poor anti-tumor immunity. We hypothesized that local delivery of tumor antigen-specific T-cells into the resection cavity following surgery would direct T-cells to residual antigens in the margins and draining lymphatics and present a platform for T-cell-targeted immunotherapy. We loaded T-cells into a biomaterial that conformed to the resection cavity and demonstrated that it could release T-cells that retained their functional activity in-vitro, and in a HNSCC model in-vivo. Locally delivered T-cells loaded in a biomaterial were equivalent in control of established tumors to intravenous adoptive T-cell transfer, and resulted in the systemic circulation of tumor antigen-specific T-cells as well as local accumulation in the tumor. We demonstrate that adjuvant therapy with anti-PD1 following surgical resection was ineffective unless combined with local delivery of T-cells. These data demonstrate that local delivery of tumor-specific T-cells is an efficient option to convert tumors that are unresponsive to checkpoint inhibitors to permit tumor cures.
ABSTRACT
BACKGROUND: Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone. METHODS: The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment. RESULTS: Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated. CONCLUSION: These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer. TRIAL REGISTRATION NUMBER: This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.
Subject(s)
Head and Neck Neoplasms/therapy , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy , Neoadjuvant Therapy , Nivolumab/therapeutic use , Radiosurgery , Squamous Cell Carcinoma of Head and Neck/therapy , Aged , Dose Fractionation, Radiation , Female , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/pathology , Humans , Immune Checkpoint Inhibitors/adverse effects , Immunotherapy/adverse effects , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoplasm Staging , Nivolumab/adverse effects , Oregon , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Radiosurgery/adverse effects , Radiotherapy, Adjuvant , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/pathology , Time Factors , Treatment OutcomeABSTRACT
Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRß sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.