The Sentinel


Saturday, November 9, 2019

SITC 2019 Scientific Highlights - Nov. 8

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 8, 2019, sessions of the 34th Annual Meeting.

Multiplexed ion beam imaging visualizes gastric irAEs

Gastric toxicity associated with PD-1 blockade therapy revealed by multiplexed ion beam imaging

Abstract O63

A gastric biopsy taken from a patient with nivolumab-associated gastroenteritis was analyzed using multiplexed ion beam imaging (MIBI) by Selena Ferrian, PhD (Stanford University) and colleagues. In order to develop a better understanding of the pathophysiology of this immune-related adverse event, twenty-seven labels were analyzed in a single upper gastric biopsy specimen.

The MIBI analysis visualized markers that were consistent with gastritis and revealed that interferon-gamma was being produced by gastric epithelial cells, rather than by immune cells. The tissue was characterized by a mixed inflammation profile, including both granzyme B-diminished/negative CD8 and FoxP3-diminished/negative CD4 T cells, with the majority of the T cells being CD4+. The investigators defined a set of features found in PD-1-associated gastritis, which included intense immune infiltrate into the lamina propria, interferon-gamma production by glandular epithelial cells, and high Ki67 expression by the epithelial cells as well. This in-depth study of a common immune-related adverse event may thus provide insight into the mechanisms of side effects and guide further immune checkpoint inhibitor development, through elucidating the mechanisms of inflammation and providing future drug targets.

CD27 T cell stimulation combination shows promise

Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors

Abstract O83

An anti-CD27 antibody, MK-5890, was tested in solid tumor patients in a study presented by Ronnie Shapira-Frommer, MD (Oncology Institute, Sheba Medical Center). Patients received either MK-5890 monotherapy or MK-5890 and pembrolizumab combination therapy, and monotherapy patients were eligible for cross-over upon disease progression. Endpoints of this study included safety and tolerability, with a secondary evaluation of objective response rate.

Forty-four patients were enrolled in the study: 25 received initial MK-5890 monotherapy at doses from 2-700 mg, while 19 were allotted to MK-5890 (200 mg) plus pembrolizumab.  Dose-limiting toxicities were observed in three of the monotherapy patients and one patient with the combination, all of which were related to infusion reactions. Over 90% of patients experienced some level of treatment-related adverse event, and grade 3-4 events were reported in 22.7% of the total population. In these initial cohorts, one patient in each group achieved a partial response. In monotherapy patients that then crossed over to the combination, adverse events were reported by 85%; at the same time, two of these patients exhibited a complete response, and another three partial responses with the median duration of the response not reached. Thus, costimulation of T cells through an anti-CD27 antibody may help improve anti-tumor activity of other therapies with further optimization, and the sequencing of CD27 stimulation appears to play a role in this efficacy.

PD-1-refractory patients may respond to TLR9 agonist

Durable responses in anti-PD-1 refractory melanoma following intratumoral injection of a toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab

Abstract O85

John M. Kirkwood, MD (University of Pittsburgh Medical Center) presented the results of a phase 1b study of pembrolizumab in combination with a TLR9 agonist, CMP-001, in patients with advanced PD-1 refractory melanoma. The majority of patients received combination pembrolizumab and CMP-001 (N=144), while a few were administered CMP-001 alone and allowed to cross-over (N=24). CMP-001, which is a CpG-A TLR9 agonist packaged into a virus-like particle, was intratumorally administered, and safety and efficacy were assessed.

The therapy was tested using a dose escalation/expansion strategy, with initial doses ranging from 1-10 mg CMP-001 (N=44), a first expansion cohort using 5 or 10 mg (N=69), and a second expansion using 10 mg (N=31). CMP-001 was also administered at two concentrations in the first expansion cohort. Overall, the treatment was well-tolerated, with the most common related adverse events being low-grade flu-like symptoms, and six patients discontinuing treatment due to adverse events. Across all cohorts, the ORR was 25%, while, among those receiving the diluted CMP-001 formulation, the ORR was 11%. Responses were noted in non-injected tumors, and, among those responding to the combination therapy, the median duration of response had not yet been reached. Response rates were similar whether a patient received monotherapy or the combination; however, the monotherapy responses were less durable. This combination therapy therefore holds promise to reverse PD-1 resistance in advanced melanomas, potentially through induction of an anti-viral immune reaction that is then able to eradicate tumors.

Prognostic B cell biomarkers identified

B-cell activated by checkpoint blockade immunotherapy and radiation improve overall survival in squamous cell carcinomas

Abstract O12

The importance of B cells in responses to immunotherapy and other cancer therapies was emphasized by Sangwoo Kim, BA (University of California – San Diego). This study evaluated B cell responses and biomarkers in HPV-associated head and neck cancer patient samples as well as in preclinical models. Proteomics arrays and RNA sequencing were employed in human samples (data from the Cancer Genome Atlas), while murine B cell responses were analyzed using BCR sequencing, flow cytometry, and single-cell RNA sequencing after combination treatment with radiotherapy and anti-PD-1 therapy.

The combination therapy in preclinical models was found to impact many aspects of B cell activity: systemic B cell activation, T1 and T2-type B cells, memory cells, plasma cells, and antigen specificity were all altered after the treatments. Specifically, BCR sequencing showed that combination therapy increased the maximum productive frequency and clonality, and also modified the CDR3 length. Increases in B cell germinal center development were also noted through single-cell RNA sequencing, with increasing density resulting from increasing treatment: more cells with a germinal center phenotype were observed with combination treatment over each individual monotherapy. In patient samples, combination therapy was found to increase IgG levels. Traditionally, HPV+ patients have demonstrated enhanced outcomes over their HPV- counterparts; however, this significance was abrogated after CD19 (marker for B cells) was taken into account, indicating that B cells play a major role in responses. For these reasons, the role of B cells in cancer biology and immunotherapy responsiveness merits further investigation and consideration, and development of adequate mouse models will be critical to achieving that goal.

Urinary microbiome linked to BCG response

Variation in the commensal urinary microbiome is associated with response to Bacillus Calmette-Guérin (BCG) immunotherapy in early stage urothelial bladder cancer

Abstract O67

The impact of the urinary microbiome on responses to intravesicular BCG therapy was investigated by Randy Sweis, MD (University of Chicago) and colleagues. Patients receiving BCG therapy experience a similar problem as has been observed with other immunotherapies: up to 50% of patients recur or progress within five years. Therefore, responsiveness to BCG therapy merits further investigation, as in this study. Sterile catheterization was employed to collect urine samples, and these samples were analyzed using 16S rRNA gene sequencing and shotgun sequencing for their microbial contents. Some samples were also analyzed for cytokine levels.

Thirty-one patients were enrolled and followed for a median of 12 months. In that time, 32% of patients recurred after transurethral resection and BCG instillation. Across all patients, the major phyla included Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes; however, distance matrix calculation revealed differences between patients with and without recurrence. Specifically, a higher abundance of Proteobacteria was found in recurring patients (P=0.035), with specific taxa showing even larger differences. At the same time, patients without a recurrence displayed higher levels of Firmicutes (P=0.049). Cytokine analysis in a subset of 13 patients revealed no significant differences between recurring and non-recurring patients. Therefore, the urinary microbiome may indeed have significant impact on the effectiveness of BCG therapy, just as the gut microbiome has been implicated with the effectiveness of other treatments.

CD73 antibody demonstrates immunomodulatory capabilities

Immunobiology and clinical activity of CPI-006, an anti-CD73 antibody with immunomodulating properties in a phase 1/1b trial in advanced cancers

Abstract O40

Phase 1 studies of an anti-CD73 antibody, CPI-006, were presented by Jason Luke, MD, FACP (University of Pittsburgh Medical Center), both as a single agent and in combination with ciforadenant. CPI-006 was administered every three weeks to patients with progressive cancer at doses from 1 to 24 mg/kg, with ciforadenant at a fixed 100 mg orally BID. The immunomodulatory activity of CPI-006 was evaluated through blood analysis of lymphoid subsets, IgH sequencing, and immunohistochemical analysis of tumor biopsies. 

Twenty-four patients received CPI-006 monotherapy, while sixteen received the combination. All-grade adverse events occurred in 75% of patients on both regimens, and grade 3-4 events in less than 17% of patients in both groups. A maximum tolerated dose was not determined. Through tissue occupancy studies, sustained CD73 occupancy in the periphery was found at doses at or above 6 mg/kg, and full tumor occupancy at 18 mg/kg or higher doses. Levels of circulating B and T cells were diminished 30 minutes after infusion, with B cells partially returning three weeks later, and T cell levels fully recovering. In alignment with a humoral immune response, the returning cells had a higher level of memory B cells than before treatment. In patients receiving at least 6 mg/kg CPI-006, tumor reductions were noted in 4/9 patients with RCC, NSCLC, or mCRPC, while no responses were noted in cancers without previous demonstration of sensitivity to these treatments. In addition to its therapeutic potential, the authors hypothesized that treatment with CPI-006 may provide opportunities for identification of novel anti-tumor antibodies due to the induced B cell dynamics.

EGFR-mut NSCLC patients may benefit from neoantigen vaccination

Neoantigen vaccination targeting shared epidermal growth factor receptor (EGFR) mutations induces clinical and immunological responses in non-small cell lung cancer patients

Abstract O18

Gregory A. Lizee, PhD (MD Anderson Cancer Center) presented a phase 1 trial of personalized neoantigen vaccination in non-small cell lung cancer patients. Peptides for vaccination were selected from predicted mutation-encoding neoantigens amongst 508 screened cancer-associated genes. Each of the 24 enrolled patients received at least 12 weekly immunizations in combination with topical imiqimod, and, if EGFR mutation positive (N=16), also had the option to continue on EGFR inhibitors.

Clinical responses were observed in seven patients on the study, all of whom were EGFR mutation-positive. Of these responses, 5/7 displayed T cell responses specific to EGFR neoantigens, and three also had responses to the L858R driver mutation.  The treatment regimen was well tolerated, and no adverse events of Grade 2-5 were observed. For EGFR mutation-positive patients, continuing on EGFR inhibitors was strongly associated with longer overall survival (13.8 vs 7.6 months for continuing vs stopping therapy, P=0.038), indicating a possible synergy between vaccination and EGFR inhibition. Therefore, vaccination may be able to overcome resistance to EGFR inhibitors in NSCLC patients.

Novel CD4+ T cell-DC interactions may lead to increased T cell activity in virally induced cancer

Intratumoral CD163+ DC amplify the type 1 immune response of CD4+CD161+ T cells in HPV16-associated cancers and are associated with better survival

Abstract O44

Several immune cell subtypes were analyzed in HPV16-associated cancers by Chantal Duurland, PhD (Leiden University Medical Center) and colleagues. HPV+ patients have increased survival compared to HPV- patients, thus the role of the immune response to these cancers should be better elucidated. High levels of CD4+CD161+ infiltrating T cells have been found in HPV+ tumors; therefore, the authors used a multi-level approach to understanding the importance of this unique subset of CD4+ T cells in the HPV+ tumor microenvironment. The authors also described a population of CD14-CD33-CD163+ cells, which were identified as dendritic cells (DCs). This subset of DCs was found to associate with strong T cell infiltrates and improved patient survival, similar to CD4+CD161+ T cells. Thus, there was an effort to understand the crosstalk of these two immune subsets in HPV+ disease. Further analyses demonstrated that activated CD163+ DCs generated higher levels of both IL-12 and IL-18 compared to their CD163- counterparts, which in turn induced a type 1 immune response by T cells. Likewise, supplementing patient-derived HPV16-specific CD4+ T cells with IL-12 and IL-18 enhanced their ability to produce interferon-gamma, and this was enhanced compared to the CD4+CD161- T cells. Thus, IL-12 and IL-18 produced by CD163+ DCs can increase stimulation of CD4+CD161+ T cells within the tumor microenvironment, which could ultimately contribute to the improved outcomes of patients with virally induced cancers. This study emphasizes the importance of studying other immune subsets in patient tumors that may ultimately lead to novel immunotherapeutic combinations.

Activated natural killer cell therapy may help Merkel cell patients

Final results from a phase 2 study using off-the-shelf activated natural killer (aNK) cells in combination with N-803, an IL-15 superagonist, in patients with metastatic Merkel cell carcinomaimaging

Abstract O19

Shailender Bhatia, MD (University of Washington) discussed a study of activated natural killer cells (aNK) in patients with Merkel cell carcinoma (MCC). The cellular therapy employed in this trial originated from a rare NK cell lymphoma, and required on-site expansion and activation by irradiation prior to administration. While MCC often responds to PD-1 blockade, nearly half of MCC patients display downregulation of MHC-I or other immune evasion mechanisms, causing them to be refractory to immune checkpoint therapy. Therefore, this group explored the use of aNK cell therapy in this population, as this treatment option is effective even in the absence of MHC-I.

Seven patients were treated – three with aNK therapy alone, and another four with aNK and N-803 (an IL-15 superagonist) combination therapy. The therapy was well-tolerated, without any treatment-related adverse events over grade 2. Two of the seven patients experienced objective responses. One patient, refractory to pembrolizumab, achieved a complete response on aNK monotherapy; however, after six months, the patient then relapsed. Re-challenge with pembrolizumab after this relapse resulted in a complete response ongoing at 36 months. These promising initial findings have led the investigators to begin other trials related to the aNK therapy as well, without the requirement for on-site processing to aid in the treatment’s feasibility.

Single-cell RNAseq links T follicular helper cells to improved outcomes in HNSCC

Transcriptional dissection reveals antitumor role of T follicular helper cells in head and neck cancer

Abstract O42

Anthony R. Cillo, PhD (University of Pittsburgh) and colleagues performed single-cell RNAseq analysis of more than 130,000 CD45+ cells sorted from PBMCs and TILs of immunotherapy-naive HNSCC patients both with and without HPV infection, as well as samples from healthy donors.

A unique T follicular helper (TFH)-like gene expression signature was observed in CD4+ Tconv cells in TILs from HPV positive patients whereas a mainly effector-memory signature was detected in TILs from HPV- patients. Immunofluorescence analysis showed tertiary lymphoid structures in HPV+ patient samples, further implicating a role for TFH in HNSCC. Analysis of patient data from the cancer genome atlas revealed that a high TFH signature was associated with extended progression-free survival, even after an multivariate analysis controlling for 9 covariates (hazard ratio=0.041, p=0.02). The increased understanding of the immune microenvironment of HNSCC from this study may provide guidance for development of future immunotherapies.

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