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Letter from the Editor

Dear JITC Readers,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

JITC Editor Picks

CLINICAL SIGNIFICANCE OF PLASMA-FREE AMINO ACIDS AND TRYPTOPHAN METABOLITES IN PATIENTS WITH NON-SMALL CELL LUNG CANCER RECEIVING PD-1 INHIBITOR: A PILOT COHORT STUDY FOR DEVELOPING A PROGNOSTIC MULTIVARIATE MODEL

Koichi Azuma, Huihui Xiang, Tomoyuki Tagami, Rika Kasajima, Yumiko Kato, Sachise Karakawa, Shinya Kikuchi, Akira Imaizumi, Norikazu Matsuo, Hidenobu Ishii, Takaaki Tokito, Akihiko Kawahara, Kenta Murotani, Tetsuro Sasada, Yohei Miyagi, Tomoaki Hoshino
Journal for ImmunoTherapy of Cancer 2022;10:e004420 (15 May 2022)

Research

Summary:

Blood-based biomarkers to predict benefit with checkpoint blockade are lacking. Reasoning that altered amino acid metabolism plays important roles in tumor development and proliferation, Koichi Azuma and colleagues conducted a single cohort observational study to determine the predictive value of serum metabolites in patients with non-small cell lung cancer receiving anti-PD-1 monotherapy. Peripheral blood samples were collected from 53 patients prior to initiation of nivolumab or pembrolizumab and plasma concentrations of amino acids and metabolites were assessed by liquid chromatography–mass spectrometry. Higher pretreatment serum concentrations of glycine, histidine, threonine, alanine, citrulline, arginine, and tryptophan significantly correlated with improved overall survival as did lower concentrations of the IDO metabolite 3h-kynurenine, as well as anthranilic acid, and quinolinic acid. A multivariate model based on serine, glycine, arginine, and quinolinic acid efficiently stratified patients by survival. Peripheral blood mononuclear cells isolated from patients identified as high risk by the multivariate model displayed transcriptomic signatures enriched for expression of loci related to immune responses, including CD8⁺ T cell activation and proliferation as well as proinflammatory responses. Concomitantly, patients classified as low-risk by the multivariate model had abundant CD8⁺ T cells, follicular helper T cells, and M1 macrophages. A total of 429 differentially expressed genes in immune cells were identified between the high-risk and low-risk groups by the model, including 20 genes involved in amino acid metabolism. A trial is ongoing to further optimize and validate the model in a larger multicenter cohort study and expand the analysis to patients receiving combination chemotherapy and anti-PD-1.

A2B ADENOSINE RECEPTOR ANTAGONISTS RESCUE LYMPHOCYTE ACTIVITY IN ADENOSINE-PRODUCING PATIENT-DERIVED CANCER MODELS

Research

Summary:

Adenosine in the hypoxic tumor microenvironment impairs effector function and proliferation of T and natural killer (NK) cells and four antagonists of the high-affinity A_2AAR adenosine receptor are currently being advanced through clinical trials. Based on recent evidence for an important role of other receptor subtypes in promoting tumor proliferation, angiogenesis, cell invasion, and metastasis, Apple Hui Min Tay and colleagues synthesized six novel adenosine receptor antagonists to demonstrate that inhibition of the lower affinity A_2BAR may be a promising immunotherapy strategy. All six novel antagonists bound with low nanomolar affinity and excellent selectivity. A_2BAR antagonism in the presence of adenosine rescued the in vitro proliferation of naïve and effector CD8⁺ T cells, central and effector memory CD4⁺ T cells, and NK cells as well as restored interferon gamma production and CD69 expression. In patient-derived breast tumor spheroids comprised of roughly 73% cancer cells and 11% immune cells, three of the six novel antagonists markedly reduced viability and slowed growth. Antagonism of A_2BAR in patient-derived sarcoma spheroids with high levels of adenosine production led to enhanced infiltration by autologous tumor infiltrating lymphocytes. These data provide a foundation for further development and preclinical evaluation of A_2BAR antagonists as a strategy to alleviate adenosine-mediated immunosuppression.

SALT-INDUCIBLE KINASE 3 PROTECTS TUMOR CELLS FROM CYTOTOXIC T-CELL ATTACK BY PROMOTING TNF-INDUCED NF-KAPPA B ACTIVATION

Research

Summary:

Resistance to immunotherapy may arise via tumor cell-intrinsic unresponsiveness to cytotoxic effectors such as perforin and granzyme B or cytokines such as interferon gamma and tumor necrosis factor alpha that arises through mechanisms that remain poorly characterized. Antonio Sorrentino and colleagues identify salt-inducible kinase 3 (SIK3) as a key tumor cell modulator of tumor necrosis factor alpha cytotoxicity via augmentation of a pro-survival and anti-apoptotic gene expression program mediated by nuclear family kappa B. SIK3 was a top hit among 108 genes that protected pancreatic ductal adenocarcinoma tumor cells from lysis in co-culture with T cells in a small interfering RNA screen. Pharmacologic inhibition of SIK3 enhanced in vitro tumor cell killing by T cells in a dose-dependent manner and stable knockdown of SIK3 in melanoma cells resulted in slower tumor growth in mice treated with tumor-infiltrating lymphocytes. Exposure to tumor necrosis factor alpha was necessary and sufficient for enhanced killing in SIK3 deficient cells—blockade of TRAIL and FasL had no effect. More than 6,000 open chromatin regions were lost in SIK3-silenced cells upon tumor necrosis alpha stimulation, particularly nuclear factor kappa B-regulated loci. Depletion of SIK3 led to reduced tumor necrosis factor alpha-induced IKK phosphorylation with a concomitant increase in acetylation of nuclear factor kappa B. Silencing of histone deacetylase 4 rescued sensitivity to tumor necrosis factor alpha in SIK3-depleted cells. The study identifies a novel, pharmacologically targetable SIK3-dependent pathway involved in tumor resistance to T cell killing.

EFFICACY OF PEMBROLIZUMAB IN PATIENTS WITH ADVANCED CANCER OF UNKNOWN PRIMARY (CUP): A PHASE 2 NON-RANDOMIZED CLINICAL TRIAL

Summary:

Metastatic cancer of unknown primary origin is a rare disease with poor prognosis and very few treatment options for tumors that are not microsatellite instability or tumor mutational burden high. Kanwal P Raghav and colleagues report tolerability and disease control with anti-PD-1 in the first clinical trial evaluating pembrolizumab for the treatment of previously treated cancer of unknown primary origin. The primary endpoint was non-progression rate at 27 weeks by immune-related RECIST criteria with key secondary endpoints including objective response rate (ORR), safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Slightly more than half of the 25 evaluable patients (out of a total of 29 enrolled in the cancer of unknown primary cohort of this basket trial for rare tumors) had poorly differentiated carcinoma and the participants had received a median of two prior lines of therapy. At a median follow up of 27.3 months, the rate of non-progression at 27 weeks was 28% (7 patients). The ORR was 20% with five patients achieving a partial response with a median DOR of 14.7 months. Median PFS and OS were 4.1 and 11.3 months. Treatment-related adverse events were overall consistent with the previously reported safety data for pembrolizumab, with only one patient requiring treatment discontinuation due to immune-mediated kidney injury. No biomarkers predicted non-progression at 27 weeks, but PD-L1 staining and tumor-infiltrating lymphocytes were associated with objective response. The data are consistent with earlier reports of responses to nivolumab in cancers of unknown primary and highlight a need for further biomarker development to efficiently select patients for immunotherapy treatment for this challenging malignancy.  

Cancer Immunotherapy Month™ 

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From the Vault

Throughout the journal’s celebratory 10^th anniversary year, this From the Vault special feature will highlight influential papers covering the wide variety of content the journal has published to advance the field. 

MANAGING TOXICITIES ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITORS: CONSENSUS RECOMMENDATIONS FROM THE SOCIETY FOR IMMUNOTHERAPY OF CANCER (SITC) TOXICITY MANAGEMENT WORKING GROUP

THE SOCIETY FOR IMMUNOTHERAPY OF CANCER CONSENSUS STATEMENT ON IMMUNOTHERAPY FOR THE TREATMENT OF MULTIPLE MYELOMA

THE SOCIETY FOR IMMUNOTHERAPY OF CANCER CONSENSUS STATEMENT ON THE IMMUNOTHERAPY FOR THE TREATMENT OF SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

THE SOCIETY FOR IMMUNOTHERAPY OF CANCER CONSENSUS STATEMENT ON THE IMMUNOTHERAPY FOR THE TREATMENT OF ADVANCED RENAL CELL CARCINOMA