Blogs

Welcome to the latest edition of the JITC Digest. It’s August, which means that our Peer Review Mentorship Program is now collecting applications from early career professionals to participate as mentees in the upcoming new class. The first year of the program, currently underway, has been a smashing success, and we’re excited to expand the number of opportunities to help train the next generation of researchers that will keep the field moving forward. You can learn more about the program and how to apply below in the special feature. 

For those of you more established in your career, there is less than one month remaining to apply to be the next JITC Editor-in-Chief. If you are an active, well-known and well-regarded scientist, academic, or clinician, I encourage you to consider applying for this inspiring and rewarding position. 

As the journal collects applications for these important roles, we also take a look at some of the science being applied across the research spectrum. Kanako Shimuzu and colleagues demonstrate how a therapeutic cancer vaccine combined with CD122-biased IL-2Cx may serve as a promising strategy for patients with advanced cancers. Feifei Wei et al developed a highly accurate, reproducible machine learning-based platform that predicts the immune checkpoint inhibitor response of patients with non-small-cell lung cancer. Check out these featured articles and more in this month’s Digest

JITC Editor Picks

Combination of cancer vaccine with CD122-biased IL-2/anti-IL-2 Ab complex shapes the stem-like effector NK and CD8+ T cells against tumor

The authors assessed CD25- and CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2Cx), which may be more effective and less toxic than traditional IL-2 therapy, in combination with a cellular CD1d/invariant natural killer T (iNKT) ligand complex/target antigen protein Wilms’ tumor 1-expressing vaccine to augment both NK and antigen-specific T cells in an advanced leukemic model. The CD122-biased IL-2Cx plus vaccine combination demonstrated 100% survival, activated iNKT 1 cells, increased distinct NK and CD8⁺ T cell subsets with stem-like phenotypes (CD27⁺Sca-1^hi, CXCR3^hi, CD127⁺TCF-1⁺T-bet⁺ Eomes⁺), and maintained long-term memory CD8⁺ T cells capable of antitumor activity. This IL-2Cx plus vaccine combination potentiates both innate and adaptive immunity and offers a promising strategy to overcome immune resistance created by the paucity of NK and CD8+ T cells observed in advanced cancers.     

Machine learning for prediction of immunotherapeutic outcome in non-small-cell lung cancer based on circulating cytokine signatures

Research

Summary:

The authors used ensemble learning random survival forest classifiers to select predictive circulating plasma cytokines collected from the peripheral blood of patients with non-small cell lung cancer (NSCLC) receiving anti-PD-(L)1 immune checkpoint inhibitors (ICI) with or without chemotherapy at baseline and 6 weeks following treatment. By incorporating additional features such as age, sex, stage, BMI, blood albumin, neutrophil-to-lymphocyte ratio, tumor PD-L1 expression, and treatment option (when applicable), the resulting advanced Cytokine-based ICI Response Index (CIRI) identified patients with worse overall survival (OS) in independent training and validation cohorts, with population-level validation cohort prediction concordance indices of 0.764 (pre-treatment) and 0.757 (on-treatment) and patient HRs of 0.141 (p<0.0001; pre-treatment) and 0.158 (p=0.038; on-treatment). Although baseline tumor PD-L1 expression failed to predict OS, this advanced CIRI model accurately and reproducibly predicted survival for patients with NSCLC both prior to and early on ICI treatment, and larger, prospective validation cohort testing of the CIRI model is needed.  

Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer

Summary:

Using a combination of (murine-adapted) talimogene laherparepvec (T-VEC) and radiation therapy (RT) in human and mouse melanoma cells, the authors observed enhanced melanoma cell death in vitro, decreased tumor growth in vivo, over either therapy alone. This doublet was associated with upregulation of PD-L1 (CD274) on gene expression profiling, and increased tumor-infiltrating CD45⁺ immune cells and (tumor-specific) CD8⁺ T cells with a decrease in T regulatory cells associated with therapeutic response. Response to T-VEC plus RT was dependent on IL-1α as evidenced by depletion of IL-1α resulting in significantly reduced therapeutic efficacy and intratumoral administration of recombinant stimulatory IL-1α recapitulating the antitumor effect. Although PD-L1 antibody treatment alone did not affect tumor growth, the addition of PD-L1 blockade to T-VEC plus RT (triple therapy) further reduced tumor growth and prolonged host survival, an effect that was also observed when a single patient with cutaneous squamous cell carcinoma metastatic to the lung received triple therapy and experienced prolonged disease control and survival.  

Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment

Summary:

MISTRG mice, in which the M-CSF (CSF1), CSF2/IL3, SIRPA, THPO genes have been humanized on a RAG2−/−, IL2RG−/− immunodeficient background, are able to generate functional human immune cells but have limited efficiency for engraftment of human-derived bone marrow hematopoietic stem and progenitor cells (HSPCs). Prior to transfer of patient-derived xenograft (PDX) tissue, the authors were able to efficiently engraft MISTRG6 mice (in which the interleukin-6 gene has been humanized) with HSPCs derived from bone marrow aspirate collected at the bedside from patients with solid tumors. These autologous MISTRG6 PDX mice generated a fully genetically matched tumor microenvironment, including innate and adaptive immunity, and offer a promising pre-clinical platform for drug development.