JITC Digest August 2021

JITC Editor Picks

Tumor rejection in Cblb^-/- mice depends on IL-9 and Th9 cells

Journal for ImmunoTherapy of Cancer 2021;9:e002889 (6 July 2021)
Research

Summary:

The intracellular checkpoint Casitas B lymphoma-B (Cbl-b) has been shown to not only negatively regulate T cell receptor signaling in cytotoxic lymphocytes, but also to suppress the differentiation of IL-9-producing T helper (Th9) cells. Building on the established roles for Cbl-b and IL-9 in anti-tumor immunity, Oliver Schanz and colleagues demonstrate that Cbl-b restricts Th9 differentiation and effector function in vitro and in vivo. In vitro differentiation yielded much higher frequencies of Th9 cells and far fewer regulatory T cells (Tregs) in a homozygous Cbl-b-deficient background compared to wild-type-derived cells. Despite fewer numbers, no defects in Treg suppressive function were seen in Cbl-b-deficient cells. Loss of Cbl-b led to increased IL-9 production by Th9 cells, and neutralization of IL-9 in culture rescued Treg frequencies. Single-cell RNA sequencing revealed enhanced upregulation of pathways associated with T cell activation and cytokine stimulation in Th9 cells lacking Cbl-b. In murine B16F10-OVA melanoma models, adoptive transfer of OVA-specific Th9 cells minimally decreased tumor growth and did not prolong survival whereas mice treated with OVA-specific Th9 cells lacking Cbl-b had smaller tumors and significantly longer survival. No significant differences in direct tumor cell killing in vitro between Cbl-b-deficient and parental cells was observed, and blocking IL-9 with a neutralizing antibody restored tumor growth in vivo. The findings reveal Cbl-b as a possible target to promote Th9 over Treg differentiation and established IL-9 as key to antitumor activity in Cbl-b-deficient backgrounds, knowledge that may be useful for future cell therapies.

Direct identification of neoantigen-specific TCRs from tumor specimens by high-throughput single-cell sequencing

Research

Summary:

Isolation of neoantigen-specific T cell receptors (TCRs) is typically technically demanding, time-consuming, and labor-intensive, requiring several weeks of long-term culture to expand tumor-infiltrating lymphocyte (TIL) pools for screening. Taking advantage of high-throughput single-cell technology, Yong-Chen Lu and colleagues developed a new approach to isolate neoantigen-specific TCRs directly from tumor specimens. The new pipeline involved direct sorting of CD4⁺PD-1⁺ and CD8⁺PD-1⁺ TILs from tumor samples followed by stimulation with neoantigen-loaded dendritic cells and single-cell analysis of target-enriched TCRs and T cell activation markers (IL-2 and interferon gamma). TCRs were isolated from three tumor samples from patients with metastatic melanoma and an additional three patients with colorectal cancer. After isolation, full-length TCRs were synthesized for transduction into autologous T cells from the patients’ peripheral blood, which were then cocultured with dendritic cells pulsed with 25-mer peptide libraries to determine specificity for mutated and parental epitopes. Analysis of combined single-cell data from tumor samples showed that the neoantigen-specific TCR clones represented small fractions of the overall population. This proof of concept sets the stage for future adoptive cell therapy approaches based on engineered T cells transduced with neoantigen-specific TCRs.

Neoantigen vaccination induces clinical and immunologic responses in non-small cell lung cancer patients harboring EGFR mutations

Fenge Li, Ligang Deng, Kyle R Jackson, Amjad H Talukder, Arjun S Katailiha, Sherille D Bradley, Qingwei Zou, Caixia Chen, Chong Huo, Yulun Chiu, Matthew Stair, Weihong Feng, Aleksander Bagaev, Nikita Kotlov, Viktor Svekolkin, Ravshan Ataullakhanov, Natalia Miheecheva, Felix Frenkel, Yaling Wang, Minying Zhang, David Hawke, Ling Han, Shuo Zhou, Yan Zhang, Zhenglu Wang, William K Decker, Heather M Sonnemann, Jason Roszik, Marie-Andree Forget, Michael A Davies, Chantale Bernatchez, Cassian Yee, Roland Bassett, Patrick Hwu, Xueming Du, Gregory Lizee
Journal for ImmunoTherapy of Cancer 2021;9:e002531 (8 July 2021)
Research

Summary:

Fenge Li and colleagues report a phase I trial of personalized neoantigen peptide vaccination for the treatment of 24 patients with non-small cell lung cancer (NSCLC) that had progressed following multiple prior therapies. To generate the vaccines, mutational profiling was performed on a panel of 508 known cancer-associated genes using DNA from needle-biopsied fresh tumor tissue and peptides were chosen based on predicted binding affinity of mutation-encoding neoantigens to individual HLA class I and class II allotypes. Vaccines were delivered as weekly subcutaneous injections with saline as a vehicle and topical imiquimod after each immunization to provide toll-like receptor 7 adjuvanting. No treatment-related adverse events were observed other than transient rash, fatigue, and/or fever in three patients. Median progression-free and overall survival were 6.0 and 8.9 months, respectively, with seven objective responses by RECIST. All of the seven patients with objective responses had EGFR-mutated tumors and vaccine-induced T cell responses against EGFR neoantigen peptides were detected in five of the seven patients. Analysis of pre- and post-treatment tumor-infiltrating lymphocytes and peripheral blood mononuclear cells from a responding patient revealed a large number of pre-existing neoantigen-specific clones prior to immunization. In vitro, EGFR inhibition increased transcription of genes associated with TRAIL signaling, antigen presentation, and CXCL1, CXCL2, and CCL2 chemokines in lung cancer cells, providing evidence for a potential mechanism of synergy with the neoantigen vaccine.

Immune-related adverse events associated with immune checkpoint inhibitors: a call to action for collecting and sharing clinical trial and real-world data

Summary:

Immune checkpoint inhibitors (ICIs) are now the standard of care for numerous solid tumors and an ever-increasing number of ICIs in combinations with chemotherapies and targeted therapies are being evaluated in late-stage studies, yet a lack of appropriate data sharing on immune-related adverse events (irAEs) and non-standardized documentation of irAEs in clinical trials and real-world settings persists. To improve the diagnosis and management of irAEs, Kerry L Reynolds and colleagues issue a call to action to standardize irAE definitions, harmonize toxicity data requirements for submission of new drug applications to regulatory bodies, encourage routine and timely reporting of real-world irAE data by providers, develop new reporting technology, and make data readily accessible to fuel discovery. The article resulted from a symposium jointly convened by the US Food and Drug Administration (FDA) and Project Data Sphere, and is one component of an ongoing effort to bring stakeholders together to improve the diagnosis and management of irAEs.

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors

Summary:

Neurologic immune-related adverse events (irAEs) have a high fatality rate and a major obstacle to developing evidence-based interventions is a lack of standardized disease definitions. To develop consensus disease definitions and severity grading for neurological irAEs, Amanda C Guidon and colleagues undertook a modified Delphi process to ultimately define seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders, and irMyopathy. The definitions included core syndromes and subtypes, level of diagnostic certainty, severity grading, exacerbation of prior condition or de novo presentation, antibody association, and concurrent neurologic or non-neurologic irAEs. The definitions were developed with flexibility for increasing levels of diagnostic specificity and provide guidance for scenarios where attribution of new neurologic symptoms to an immune etiology may be challenging, such as checkpoint inhibitor combinations with chemotherapy. The framework provided in the paper not only is a key first step toward the development of evidence-based management approaches for neurologic irAEs, but also may be used as a model for future consensus definitions for irAEs affecting other organ systems.

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