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Sunday, November 10, 2019

SITC 2019 Scientific Highlights - Nov. 9

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 9, 2019, sessions of the 34th Annual Meeting.

In vivo tracking of adoptively transferred T cells enabled by PET/CT

Flexible copper-64-nanoparticle-based cell labeling system allows for in vivo tracking of adoptively transferred T-cells by PET/CT

Abstract O1

A flexible system for radiolabeling and tracking adoptive cellular therapies was presented by Hólmfridur R. Halldórsdóttir, MSc (Technical University of Denmark). By labeling T cells in vitro using copper-64 ([64]Cu) micelles, which are self-assembled lipids, the team was able to noninvasively monitor the in vivo biodistribution of these radiolabeled cells over the course of 40 hours using positron emission tomography/computed tomography (PET/CT), and track their response to various therapeutic interventions.

Prior to in vivo imaging, the impact of micelles on T cells was tested. Viability and function of the T cells were not affected by the micelles. Throughout all in vivo studies, there was correspondence between the number of T cells in an organ and the measured radioactivity, indicating the cell tracking technique could provide accurate quantification. Following whole-body irradiation, elevated activity was noted in the thymus compared to non-irradiated mice, which is a well-known homing site for T cells after total body irradiation (4.6±0.1% vs 2.1±0.1% of injected dose, respectively). Tumors were also treated with a sustained release depot of TLR7 agonist, and, following this treatment, a higher accumulation of [64]Cu-labeled T cells was observed in the tumor tissues. This approach may therefore help elucidate the in vivo behavior of adoptive cellular therapies, without compromising their efficacy, which has immense implications for future monitoring of cellular therapies.

HER2-positive cancers may benefit from novel bispecific treatment

A phase 1 dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies

Abstract O82

Sarina Piha-Paul, MD (MD Anderson Cancer Center) presented an investigation of a HER/4-1BB bispecific, known as PRS-343, in patients with HER2-positive cancers. This dose-escalation study has evaluated cohorts from 0.0005 to 8 mg/kg in order to identify the safety profile of PRS-343 and to determine the dose for further studies. Measures of response and biomarkers were among the secondary objectives.

Fifty-three patients with solid tumors have been treated to date, and the minimal active dose was found to be 2.5 mg/kg. At and above this threshold, eighteen patients have been treated and are evaluable. In this patient group, significant expansion of the CD8+ T cell pool was noted after treatment with PRS-343, especially in the tumor microenvironment, in accordance with the proposed mechanism of action for PRS-343. This led to a disease control rate in these patients of 55%, including 2/18 patients confirmed partial response. Higher expansion of CD8+ T cells was found in responding patients over non-responders. The treatment was considered safe, with no serious adverse events or dose-limiting toxicities reported. The investigators are therefore continuing the further investigation of this first-in-class 4-1BB bispecific.

Front-line atezolizumab improves PD-L1+ NSCLC outcomes

IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) monotherapy vs platinum-based chemotherapy (chemo) as first-line (1L) treatment in PD-L1-selected NSCLC

Abstract O81

PD-L1-postive NSCLC patients were treated with either front-line atezolizumab or chemotherapy in the IMpower110 study, presented by Giuseppe Giaccone, MD, PhD (Weill Cornell Medicine). In this study, both squamous and non-squamous NSCLC patients were enrolled, and randomized 1:1 to atezolizumab 1200 mg Q3W or platinum-based chemotherapy for four or six 21-day cycles. As the primary endpoint, overall survival was tested hierarchically by PD-L1 status (highest to lowest expression).

Across both arms of the trial, PD-L1 expression was evenly distributed: 37% of all-comers were TC3/IC3. The majority of patients experienced treatment-related adverse events: 60.5% of atezolizumab patients and 85.2% of chemotherapy patients reported any-grade events, with grade 3-4 in 12.9% and 44.1% as well, respectively. In patients with the highest levels of PD-L1 expression (TC3 or IC3), after a median follow-up of 15.7 months, the overall survival was significantly improved (by 7.1 months) with atezolizumab treatment over chemotherapy (HR=0.595, p=0.0106). The statistical endpoints were not met in the pre-specified next analysis group of TC2/3-IC2/3, however, so further analysis could not be performed for significance at other PD-L1 levels. Front-line atezolizumab may therefore hold promise for further exploration in highly-PD-L1-expressing NSCLC patients, who appear to derive the most benefit in this front-line study.

Microbial colonization linked to colorectal cancer immune responses

Helicobacter hepaticus remodels the tumor immune microenvironment and reduces colorectal tumor burden

Abstract O69

Based on the hypothesis that intestinal microbiota may modulate immune balance, Abigail E. Overacre-Delgoffe, PhD (University of Pittsburgh) presented a preclinical study of microbiome manipulation in colorectal cancer (CRC) models. Colitis-associated CRC was established through AOM-DSS induction, and half of these tumor-bearing mice were colonized with Helicobacter hepaticus (Hhep) after tumor development. Lymphocytes throughout the digestive tract and tumor were analyzed using flow cytometry and confocal microscopy.

Colonization of CRC tumor-bearing mice with Hhep was found to significantly remodel the tumor microenvironment, leading to increased dendritic and Tconv cell infiltration, as well as a decreased Treg presence. This also led to reduction of tumor burden and extension of overall survival for those mice supplemented with Hhep. Using FISH, Hhep was found to colonize not only the normal colonic mucosa, but also infiltrated tumors themselves as well. The authors report that the bacteria also lead to Hhep-specific CD4+ T follicular helper cell (Tfh) infiltration, which may contribute to more efficient anti-tumor immunity, particularly due to the increased number of organized tertiary lymphoid structures in the tumors. Further investigation of the microbiome may in turn provide insight and potential therapeutic mechanisms for improving anti-cancer immune responses.

Biomarkers for immunotherapy responsiveness in sarcomas defined

Immune enrichment and functional T-cell receptor (TCR) frequencies predict response to immune checkpoint blockade (ICB) in selected fusion-associated sarcomas

Abstract O33

Biomarkers of response to immunotherapy for sarcomas were analyzed and presented by Akash Mitra, BS (MD Anderson Cancer Center). Sarcoma patients (alveolar soft part and synovial) were treated with combination durvalumab and tremelimumab, and an in-depth analysis of tumor tissues was performed. Whole-exome, RNA- and TCR-sequencing were conducted to explore correlates with response.

Unlike some other cancer types, tumor mutational burden was not correlated with outcomes in this study. Rather, many immune-related pathways were upregulated in responders, as KEGG pathway analysis indicated higher activity of T cell and B cell response pathways, as well as increases in PD-L1. B cell infiltrates were also more frequent in responding tumors in both pre-treatment and on-treatment biopsies. T cell clonality was inversely correlated with outcomes, with an increased diversity in responders, and a lower maximum productive frequency in responders as well. While further immune deconvolution and BCR sequencing studies are on-going, these genetic and immune signatures may provide greater insight into the immune responsiveness of sarcomas.

Il-35+ B cells play a role in pancreatic cancer progression

IL-35+ B cells regulates anti-tumor immune response in pancreatic cancer

Abstract O47

Bhalchandra Mirlekar, PhD (University of North Carolina - Chapel Hill) presented a study of the immunologic processes that contribute to pancreatic tumor immunotherapy resistance. This involved the use of both spontaneous and orthotopic murine pancreatic tumor models, using a model with B cell-specific genetic loss of IL-35. Combination therapy of IL-35 blockade and immune checkpoint blockade was explored to further elucidate the role of IL-35.

This study uncovered an important role for regulatory B cells in the promotion of pancreatic tumorigenesis. Specifically, this cell population produced IL-35 – a cytokine which has been indicated in the suppression of T cell responses both in autoimmunity and cancer. The study further indicated that only B cell-produced IL-35 was essential for this immunosuppression to occur. When pancreatic tumors from the IL-35 deficient mouse model were treated with anti-PD-1 therapy, regression of normally immunotherapy-resistant tumors was observed. These preclinical studies were also corroborated through analysis of patient pancreatic cancer samples, in which an IL-35+ B cell subset was found, and correlated with dysfunctional T cells. IL-35-targeted therapy may therefore be promising for pancreatic cancer, but the model is still slightly disparate from the actual clinical situation. 

Bispecific anti-PD-1 and CTLA-4 antibody demonstrates promise of lower toxicity

A phase 1 study of AK104, a tetrameric bispecific antibody that targets PD-1 and CTLA-4 in patients with advanced solid tumors

Abstract O30

A dose escalation and expansion study of a PD-1/CTLA-4 bispecific antibody was presented by Ben Markman, MBBS, FRACP (Monash Medical Centre). While combination treatments of individual PD-1 and CTLA-4-targeting antibodies have shown encouraging efficacy, they are also limited by severe toxicities. Therefore, this group hypothesized that the bispecific tetrameric form of AK104 may maintain that efficacy while limiting toxicity due to enhanced tumor specificity. Patients with several solid tumor types were enrolled and dosed between 0.2 and 10 mg/kg Q2W with AK104 with the goal of determining the safety, efficacy, and recommended phase two dose of the treatment.

The bispecific agent was found to have a Kd an order of magnitude better than that of ipilimumab and nivolumab, supporting its improved targeting avidity. Fifty-five patients have been treated with a median of four doses as of data cut-off, with the most at the 6 mg/kg level. Any-grade treatment-related adverse events were reported in 63% of patients, with 11% of patients experiencing a grade 3 reaction, both of which compare favorably to the traditional combination therapy. When patients were treated with doses of at least 2 mg/kg, the overall response rate was 24%, and the disease control rate was 44%. Increases in Ki-67, a proliferation marker, were noted in peripheral CD4+ T cells after treatment with AK104, supporting immune activation. While it remains early to compare the efficacy of AK104 relative to currently-approved combination therapies, the initial safety profile of this agent warrants further investigation.

Immunologic responses noted in vaccine-treated glioblastoma

Phase II trial of therapeutic vaccine consisting of autologous dendritic cells loaded with autologous tumor cell antigens from self-renewing cancer cells in patients with newly diagnosed glioblastoma

Abstract O22

A patient-specific vaccine for glioblastoma patients, AV-GBM-1, was tested in a phase 2 study presented by Daniela Bota, MD, PhD (University of California – Irvine). The technique involved establishment of a short-term cell line from tumor tissue excised at the time of surgery, production of dendritic cells from PBMCs, and development of the vaccine antigens from irradiated tumor cell lysate. Vaccination was performed following completion of standard optimal therapy (surgical resection, radiotherapy, and chemotherapy). The study aimed to achieve a 75% survival rate fifteen months after enrollment, which would represent a 50% increase over survival from current standard therapies.

Thirty-one of the planned 55 patients have begun treatment, with success rates of 46/48 for cell line establishment and 41/42 for development of a successful leukapheresis product. To date, twelve patients completed all eight doses, and five discontinued early due to progression. Immunological responses including Th1, Th2, and Th17 responses were noted in 60% of patients for whom this was measured, indicating promising immune activation with this technique. No notable toxicities have been reported, with all serious adverse events not attributed to the treatment. The study is still ongoing, but, given the encouraging immune activation indications and safety profile so far, the authors are enthusiastic about future results.

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