The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8⁺ T cells ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8⁺ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8⁺ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.

The years since 2009 have seen tremendous progress in unlocking the curative potential of the immune system for the treatment of cancer. Much of that revolution in immuno-oncology has been fueled by the clinical success of immune checkpoint inhibitors, particularly those targeting the PD-1 axis. Unfortunately, many patients still fail to benefit from checkpoint blockade or other immunotherapies. An inability to fully activate antitumour T cells contributes in part to the failure of those therapies. Here, we review the basic biology of T cell activation, with particular emphasis on the essential role of the dendritic cell and the innate immune system in T cell activation. The current understanding of the multiple factors that govern T cell activation and how they impinge on tumour immunotherapy are also discussed. Lastly, treatment strategies to potentially overcome barriers to T cell activation and to enhance the efficacy of immunotherapy are addressed.

Background and aims: Current guidelines state that infliximab is contraindicated for the treatment of immune checkpoint inhibitor-related hepatitis (ir-hepatitis) due to the risk of inducing further liver damage. As this recommendation is largely based on the use of infliximab for rheumatologic diseases, we evaluated the efficacy and hepatotoxicity of infliximab in patients with steroid-refractory immune-related adverse events (irAEs). Methods: We retrospectively reviewed consecutive patients treated with infliximab for irAEs at Princess Margaret Cancer Centre. To assess hepatotoxicity, we compared the mean value of ALT, AST, and total bilirubin (BT) before and after infliximab treatment. We used logistic regression to assess factors associated with infliximab efficacy. Results: Between January 2010 and February 2019, 56 patients were identified. The median age of the patients was 63 (27–84) years. Colitis was the most frequent toxicity (66%), followed by pneumonitis (11%). Infliximab was used to treat ir-hepatitis in one patient. The median number of infliximab doses was 1 (1–3) and led to toxicity resolution in 43 (76%) patients. The mean ALT, AST, and BT levels before and after infliximab treatment were not statistically different. The patient treated for ir-hepatitis had a complete recovery, with no incremental liver toxicity. Conclusions: In this dose-limited setting, infliximab was effective in resolving irAEs and did not induce hepatotoxicity.

Since their approval, immune checkpoint inhibitors (ICIs) have become the standard of care for multiple malignancies. ICIs enhance tumor destruction by blocking important immunomodulatory pathways that regulate T-cell activation. These pathways include programmed cell death protein-1 and its ligands (programmed cell death protein-1 and programmed death ligand-1, respectively) and cytotoxic T-lymphocyte–associated protein 4. While blocking these pathways can enhance tumor destruction, these pathways are critical for the development of maternal tolerance towards the fetus. Therefore, if ICIs disrupt these immunomodulatory pathways, there could be a maternal immune response against the fetus, as was found in animal studies. With few reported cases of human pregnancy exposure to ICIs, the effects of ICIs on human pregnancy remain largely unknown. Here, we review and summarize the 6 cases of maternal exposure to immunotherapy that have been published before the present study. To add to the evidence, we present a case series of 2 patients who have been exposed to immunotherapy in pregnancy.

Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions that would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We evaluated investigator-assessed best overall response (BOR) and immune-related adverse events (irAEs). We correlated survival outcomes with age, performance status, immune status and irAEs. Of the 36 patients identified, the best overall response (BOR) to ICI was a partial response (PR) in 41.7%, a complete response (CR) in 27.8%, and stable disease in (SD) 13.9%. The progression-free survival (PFS) rate for 1 year was 58.1%; the median PFS was 21.3 months (95% CI 6.4–NE). The 1-year overall survival (OS) was 76.7%, and the median OS was 38.6 months (95% CI 25.4–NE). Immune-compromised patients, ECOG performance 2–3, and age ≥ 75 years were not significantly associated with PFS or OS. IrAE grades 3–4 were seen in 13.9% of patients. In our Canadian experience with real-world patients, ICI was an effective and safe treatment for advanced cSCC patients. Patients achieved great benefits with ICI regardless of age, immune status or ECOG performance status. We acknowledge the small sample size and retrospective methodology as the main limitations of our study.

Background: Immune checkpoint inhibitor-induced pancreatic injury (ICI-PI) is a rare immunotoxicity, with limited data on treatment and long-term outcomes. Methods: PubMed, EMBASE, and Cochrane Library were systematically searched for studies reporting ICI-PI in patients with solid malignancies. ICI-PI was defined as pancreatic inflammation post-ICI exposure, diagnosed via radiologic changes or elevated lipase/amylase levels without other underlying causes. The CTCAE grading system was used. The primary objectives were to assess the frequency, severity, serum abnormalities, management, and long-term outcomes. We conducted a proportional single-arm meta-analysis with a random effects model. Results: The analysis included 25 retrospective studies involving 48,704 patients. Tumor types included thoracic/head and neck (38%), skin (26%), genitourinary/gynecological (18%), gastrointestinal (12%), and others (6%). The median age ranged from 56 to 73 years, with a follow-up from 2.5 to 45.9 months. ICI-PI occurred in 3.60% (95% CI: 1.64–6.28%) of patients, with grade ≥ 3 toxicity in 59.45% (95% CI: 35.32–81.37%). The frequency rates of ICI-PI were 1.99% for CTLA4 inhibitors, 5.01% for PD(L)1 inhibitors, and 7.44% for combination ICI therapy (p < 0.01). The median time to onset from treatment initiation ranged from 30 to 390 days, and symptom resolution ranged from 55 to 84 days. Management included corticosteroids (30.20%), intravenous fluids (22.82%), and hospitalization (30.46%). Chronic complications affected 63.54% (95% CI: 29.03–91.56%), including primarily diabetes mellitus (DM 89.45%; 95% CI: 61.88–100.0%) and exocrine pancreatic insufficiency (EPI 10.55%; 95%: 0.0–38.12%). ICI-PI recurrence occurred in 27.2% of those resuming ICI therapy. The objective response rate was 61.7% (95% CI: 55.08–68.17%). Conclusions: ICI-PI, though infrequent, is severe and predisposes patients to chronic complications, including DM and EPI.