The following articles have been recommended for further reading in the field of cancer immunotherapy by Dr. Jeffrey S. Weber, Deputy Editor of the Clinical/Translational Cancer Immunotherapy section.
“Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial” by Tina Cascone et al
Immune checkpoint inhibitor therapy has become a component of the standard of care for advanced non-small cell lung cancer (NSCLC), catalyzing efforts to expand immunotherapy regimens to earlier stages of disease. Tina Cascone and colleagues report results from the phase II, randomized NEOSTAR trial investigating neoadjuvant nivolumab (anti-PD-1) or nivolumab + ipilimumab (anti-CTLA-4) therapy, including exploratory analyses characterizing immune responses to treatment. The primary endpoint was major pathologic response (MPR; ≤ 10% viable tumor, which was set based on historical neoadjuvant chemotherapy controls) in the intent to treat (ITT) population (44 randomized patients). The MPR primary endpoint was reached in the nivolumab + ipilimumab arm but not in the nivolumab monotherapy arm. Of the 37 patients with resected tumors, the MPR rates for the combination versus monotherapy were 50% and 24%, respectively, and pathologic complete response (pCR) rates were 38% and 10%, respectively. Exploratory analyses revealed correlations between perturbations in fecal microbiota and MPR rates. Further, immune profiling and T cell receptor (TCR) sequencing revealed that the nivolumab + ipilimumab combination resulted in higher levels of tumor infiltrating lymphocytes including effector, effector memory, and tissue-resident memory T cells as well as higher numbers of CD3+ and CD8+/CD3+ T cells and increased TCR clonality post-treatment. Having reached its primary endpoint, the phase II study sets the stage for further evaluation of neoadjuvant checkpoint blockade therapy for NSCLC.
Why this matters: This study reports improved MPR rates with neoadjuvant nivolumab + ipilimumab treatment compared to historical controls of neoadjuvant chemotherapy. In addition, the strong immune response is promising, given the historically high rate of recurrence in early-stage resected NSCLC tumors.
“Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion” by Ester Gangoso et al
The immunosuppressive microenvironment in glioblastoma multiforme (GBM) tumors is well established, however, the underlying mechanisms are still unknown. Ester Gangoso and colleagues developed mouse-derived GBM stem cells (GSCs), focusing on the mesenchymal, immune-evasive subtype of GBM through co-deletion of Nf1 and Pten and overexpression of EGFRvIII (NPE cells). NPE cells orthotopically transplanted into immunocompetent BL6 mice resulted in aggressive tumor growth and infiltration. Implanted NPE tumor cells from BL6 mice were isolated and serially transplanted into fresh hosts, resulting in increased tumor formation and worse survival compared to the initial tumors. This difference was not seen in serially transplanted tumors in NSG mice, indicating an immune microenvironment-induced evasion mechanism. Myeloid-derived suppressor cells, PD-1/PD-L1-expressing macrophages, and PD-1/LAG-3 expressing CD4+ and CD8+ T cell populations were higher in the microenvironment of serially transplanted tumors. Serially transplanted cells were hypomethylated at numerous loci and showed changes in gene expression in many immune-regulated genes compared to the parent cells, notably, interferon regulatory factor 8 (Irf8), normally a myeloid-specific transcription factor induced by interferon-gamma (IFNy). Both in vitro IFNy stimulation and co-culture with macrophages induced Irf8 expression in the immune-naïve NPE cells, while knocking out Ifr8in serially transplanted tumors led to similar growth kinetics as the parent clones. Molecular profiling on 36 patient-derived GSC lines identified a ‘mesenchymal immune signature’ population with a distinct IFNy signaling-associated gene expression pattern including upregulation of IFR8 and hypomethylation patterns similar to the serially passaged tumors. Altogether, this study identifies a major immune-evasion pathway in GBM mesenchymal stem cells, induced by the tumor microenvironment.
Why this matters: Mechanistic insight into the IFNy-induced immune evasion of GBM mesenchymal cells may be leveraged to hone existing immunotherapy strategies for this difficult-to-treat tumor or lead to novel immune-modulating targets.
“An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer” by Thomas Powles et al
The current standard of care for advanced urothelial cancer (AUC) that has progressed on front-line therapy is immune checkpoint blockade targeting the PD-(L)1 axis. Thomas Powles and colleagues enrolled patients with chemotherapy-refractory AUC with various targetable mutations to receive combination therapy with durvalumab (anti-PD-L1) + a relevant targeted agent in the phase I BISCAY trial. Specifically, the study investigated durvalumab with the FGFR inhibitor AZD4547 for tumors with FGFR mutations, the poly-ADP ribose polymerase (PARP) inhibitor olaparib for tumors with and without DNA homologous recombination repair deficiency, and the TORC1/2 inhibitor vistusertib for tumors with alterations to TSC1/2 and RICTOR. The trial was biomarker-driven with an adaptive design and assigned a total of 135 patients to six arms. The primary endpoint was safety, with a secondary efficacy endpoint of objective response rate (ORR) compared to historical response rates to ICI monotherapy. Circulating tumor DNA (ctDNA) was also assessed at baseline and throughout the study, demonstrating a correlation between expression of FGFR mutations and radiological response. None of the combinations met the pre-specified efficacy endpoint. Duration of response and progression-free survival were also not improved in the combination arms compared to monotherapy. Grade 3–4 adverse events occurred in 24%–48% in patients receiving a combination therapy, versus 10% with durvalumab monotherapy.
Why this matters: Although the BISCAY trial did not demonstrate superiority for the combination of molecularly targeted therapies with ICIs, there are important takeaways including lessons to inform future biomarker-based/personalized trials and the utility of ctDNA for patient selection and prognostic analyses.
“Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination” by Jiali Yu et al
The tumor microenvironment plays a major role in the response to immunotherapy. Jiali Yu and colleagues investigated if responses to immunotherapy vary by metastatic site. In patients with metastatic melanoma and non-small cell lung cancer treated with immunotherapy or targeted therapy and immunotherapy or chemotherapy, worse outcomes with checkpoint blockade occurred in cases of liver metastases compared to other organs. The association remained true independent of PD-L1 expression and tumor mutational burden (TMB) levels. The presence of liver metastases was also associated with progressive tumor growth throughout the body, indicative of systemic alterations to the immune response. In murine models with MC38 tumors transplanted into various organs, an early accumulation of tumor-specific T cells in the liver that decreased at later time points was observed when liver metastases were present. Liver metastases also were associated with increased T cell dysfunction markers and myeloid cell-induced CD8+ T cell apoptosis. A combination of liver-directed radiotherapy and anti-PD-L1 therapy diminished CD11b+F4/80+ myeloid cells, increased T cell infiltration of liver metastases, and reversed systemic immunotherapy resistance.
Why this matters: This preclinical study uncovers a strategy to overcome hepatic-induced systemic immunosuppression and improve responses to immunotherapy in patients with liver metastases.
“CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumors” by Roberta Zappasodi et al
Glucose competition occurs in the tumor microenvironment between cells that are glycolysis-dependent, including tumor cells and some immune cells. Roberta Zappasodi and colleagues demonstrate that this competition has implications on immunotherapy efficacy. In co-culture, 4T1 cells (highly glycolytic mammary carcinoma cells) outcompeted activated T cells for glucose. In samples from patients with melanoma, high expression of glycolytic genes in tumor cells negatively associated with immune infiltration. This negative correlation was reversed for most glycolytic genes after ipilimumab (anti-CTLA-4) treatment. Obstruction of glycolysis via knock down of Ldha in 4T1 cells led to enhanced immune infiltration after anti-CTLA-4 treatment. In vivo, knockdown of Ldha led to fewer intratumoral Tregs, increased CD8+ T cell infiltration, as well as elevated interferon-gamma (IFNy) and tumor necrosis factor (TNF) expression after neoadjuvant anti-CTLA-4. Importantly, enforced glycolysis altered normal Treg stability, but not in a CD28-deficient background.
Why this matters: This study uncovers metabolic determinants of Treg stabilization that can possibly be facilitated via CD28 co-stimulation by anti-CTLA-4 treatment.
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