As gut microbiota composition is an important determinant of response to immune checkpoint inhibitors (ICIs), we examined the effect of various co-medications known for their interaction with microbiota, when given at ICI initiation. We identified patients with advanced cancer treated with ICI between May 2015 and September 2017 in our institution. Co-medications given within 1 month before or 1 month after the first administration of ICI were reviewed from medical records. Survival data were analysed with univariable Cox regression, and the combined effect of multiple factors was assessed with factor analysis of mixed data (FAMD). The impact of co-medications on immune-related adverse events (irAEs) occurrence was also assessed. A total of 635 patients were included. Psychotropic drugs (41%), proton pump inhibitors (PPIs; 38%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs; 32%), glucocorticoids (26%), antibiotics (24%), statins (21%) and morphine (20%) were the most prescribed co-medications. Baseline use of antibiotics, glucocorticoids >10 mg/day, PPIs, psychotropic drugs, morphine and insulin was associated with significantly shortened overall survival and decreased tumour response, whereas coadministration of statins, ACEs and/or ARBs, non-steroidal anti-inflammatory drugs, aspirin and oral antidiabetic drugs did not impact patient outcomes. Treatments that altered the response to ICI were also associated with a decreased incidence of irAEs. FAMD revealed the respective weight of each factor or co-medication on the oncological outcomes. Co-medications must be carefully assessed at the time of ICI initiation and clinicians aware of their possible deleterious effect, notably for PPIs, glucocorticoids, antibiotics and psychotropic drugs.

A γδ TCR senses metabolic tumor reprogramming through recognition of EphA2.

PURPOSE: HER2 exon 20 insertions and point mutations are oncogenic drivers found in 1%-2% of patients with non–small-cell lung cancer (NSCLC). No targeted therapy is approved for this subset of patients. We prospectively evaluated the effectiveness of the combination of two antibodies against human epidermal growth factor 2 (HER2 [HER2] trastuzumab and pertuzumab with docetaxel; trastuzumab and pertuzumab) and docetaxel. METHODS: The IFCT 1703-R2D2 trial is a multicenter, nonrandomized phase II study. Patients with HER2-mutated, advanced NSCLC who progressed after ≥ 1 platinum-based treatment were enrolled. Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m² every 3 weeks. The primary outcome was the objective response rate (ORR). Other end points included the duration of response, progression-free survival, and safety ( NCT03845270 ). RESULTS: Forty-five patients were enrolled and treated. The median age was 64.5 years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an Eastern Cooperative Oncology Group performance status of 2, and 30% had brain metastases. The objective response rate was 29% (n = 13), and 58% had stable disease (n = 26). The median progression-free survival was 6.8 months (95% CI, 4.0 to 8.5). The median duration of response in patients with a confirmed response (n = 13) was 11 months (95% CI, 2.9 to 14.9). Grade 3/4 treatment-related adverse events were observed in 64% of the patients. No patient discontinued treatment because of toxicity. The most frequent grade ≥ 3 treatment-related adverse events were neutropenia (33%), diarrhea (13%), and anemia (9%). CONCLUSION: Triple therapy with trastuzumab, pertuzumab, and docetaxel is feasible and effective for HER2-mutated pretreated advanced NSCLC. These results highlight the effectiveness of the HER2 antibody-based strategy, which should be considered for these patients.

Innate and adaptive immune cells from myeloid and lymphoid lineages resolve host infection or cell stress by mounting an appropriate and durable immune response. Upon sensing of cellular insults, immune cells become activated and undergo rapid and efficient functional changes to unleash biosynthesis of macromolecules, proliferation, survival, and trafficking; unprecedented events among other mammalian cells within the host. These changes must become operational within restricted timing to rapidly control the insult and to avoid tissue damage and pathogen spread. Such changes occur at high energy cost. Recent advances have established that plasticity of immune functions occurs in distinct metabolic stress features. Evidence has accumulated to indicate that specific metabolic signatures dictate appropriate immune functions in both innate and adaptive immunity. Importantly, recent studies have shed light on whether successfully manipulating particular metabolic targets is sufficient to modulate immune function and polarization, thereby offering strong therapeutic potential for various common immune-mediated diseases, including inflammation and autoimmune-associated diseases and cancer. In this review, we detail how cellular metabolism controls immune function and phenotype within T cells and macrophages particularly, and the distinct molecular metabolic programming and targets instrumental to engage this regulation.

The metabolic reprogramming of tumor cells and immune escape are two major hallmarks of cancer cells. The metabolic changes that occur during tumorigenesis, enabling survival and proliferation, are described for both solid and hematological malignancies. Concurrently, tumor cells have deployed mechanisms to escape immune cell recognition and destruction. Additionally, therapeutic blocking of tumor-mediated immunosuppression has proven to have an unprecedented positive impact in clinical oncology. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune signaling through both the release of signaling molecules and the expression of immune membrane ligands. Here, we review these molecular events to highlight the contribution of cancer cell metabolic reprogramming on the shaping of the antitumor immune response.