AZUR-4, a Phase 2, Open Label, Randomized Study of Neoadjuvant Dostarlimab Plus CAPEOX Versus CAPEOX in Previously Untreated T4N0 or Stage III Mismatch Repair Proficient/Microsatellite Stable Resectable Colon Cancer

Clinical Colorectal Cancer · 2026-03-01

A tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors

Nature Biotechnology · 2025-10-17 · 18 citations

Microengineered transplantation of human solid tumors for in vitro studies of CAR T immunotherapy

bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-29 · 1 citations

Treatment of solid malignancies using chimeric antigen receptor (CAR) T cells remains a significant challenge, but current efforts to advance this therapy are challenged by our limited capacity to probe and understand cancer-immune interactions in human solid tumors. Here, we present a microengineered platform for in vitro modeling of malignant solid tumors during CAR T therapy. This system makes it possible to vascularize human tumor explants and perfuse them with blood-borne immune cells in a controlled manner. We first present a microphysiological model of human lung adenocarcinomas infused with CAR-T cells and show how this system can be used to simulate, visualize, and interrogate tumor-directed trafficking and effector function of CAR T cells. We then demonstrate the proof-of-principle of testing a chemokine-directed CAR T cell engineering strategy in a model of malignant pleural mesothelioma and validating our in vitro assessment using a matching in vivo mouse model. Finally, we describe a potential therapeutic target discovered by single-cell RNA sequencing that can be pharmacologically modulated to increase the efficacy of CAR T cells for lung adenocarcinoma, for which we also present specific biomarkers identified by global metabolomics analysis. We believe that the bioengineering principle demonstrated here will make important contributions to developing new capabilities for preclinical studies of adoptive cell therapies for cancer and other complex diseases.

AZUR-4, a phase 2, open label, randomized study of neoadjuvant dostarlimab plus capecitabine plus oxaliplatin (CAPEOX) versus CAPEOX alone in previously untreated T4N0 or stage III mismatch repair proficient/microsatellite stable resectable colon cancer.

Journal of Clinical Oncology · 2025-05-28

TPS3649 Background: Colon cancer is the third most common cancer globally, with a standard of care in the nonmetastatic setting that includes surgery followed by adjuvant chemotherapy. Results of recent clinical trials suggest that neoadjuvant therapy may be beneficial in locally advanced colon cancer. Neoadjuvant immunotherapy has shown impressive responses in mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) disease with pathological complete responses of up to 67% and 3-year disease-free survival of 100% reported in the NICHE 2 trial. However, most colon cancer (85%–90%) is mismatch repair proficient (MMRp)/microsatellite stable (MSS), which has been shown to have poor response to conventional immunotherapy. Dostarlimab, a programmed cell death protein-1 (PD-1) inhibitor, has a high affinity for binding to PD-1, blocking the interaction between PD-1 and its ligands (PD-L1 and PD-L2). Dostarlimab monotherapy has been approved in the US for the treatment of adults with dMMR advanced/recurrent solid tumors. The AZUR-4 trial (NCT06567782) evaluates dostarlimab + CAPEOX versus CAPEOX alone as neoadjuvant treatment to identify early signals of efficacy in resectable MMRp/MSS colon cancer. The study will assess the relationship between conventional and advanced blood- and tumor-based immune response to better understand the contribution of dostarlimab to pathological response. Methods: AZUR-4 is a multicenter, randomized, open-label phase 2 study in MMRp/MSS resectable colon cancer. Approximately 120 patients will be enrolled and randomized 3:1 to the dostarlimab + CAPEOX and CAPEOX arms, respectively, in which they will receive 4 cycles of Q3W neoadjuvant therapy. Key eligibility criteria include age ≥18 years, confirmed resectable MMRp/MSS colon adenocarcinoma with no prior treatment, clinically staged as T4N0 or stage III, Eastern Cooperative Oncology Group performance status of 0 or 1, and required tissue biopsies providing fresh tumor tissue either at prescreening or screening. Primary endpoints are major pathologic response rate (mPR) assessed at ≤10% residual viable tumor (RVT) and treatment-emergent adverse events (AEs), serious AEs, immune-mediated AEs, and AEs leading to death or discontinuation of study drug. Secondary endpoints include primary tumor resection not being excluded by either disease progression or treatment-related toxicities, and pathological response categories that include complete pathological response (cPR) and partial pathologic response (pPR). Exploratory endpoints include overall survival, event-free survival, effects on circulating tumor DNA dynamics, and pathological response rate in biomarker subsets. Clinical trial information: NCT06567782 .

Editor’s Note: Multiple Injections of Electroporated Autologous T Cells Expressing a Chimeric Antigen Receptor Mediate Regression of Human Disseminated Tumor

Cancer Research · 2024-11-04 · 1 citations

Supplemental Figure 6 from Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors

2023-04-03

<p>FAP-specific KIR-CAR/Dap12 T cells induce bone marrow hypocellularity and loss of body weight.</p>

Supplementary Figures 1 through 8 from Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization

2023-04-03

<p>Supplemental Figure 1. Schematic representations of viral-engineered constructs for transductions of T cells. Supplemental Figure 2. Successful transduction of primary T cells and detection of transgenes. Supplemental Figure 3. Phenotypic characterization of human CAR T cells at baseline. Supplemental Figure 4. Phenotypic characterization of murine CAR T cells at baseline. Supplemental Figure 5. Heightened cytokine production by CAR-RIAD T cells upon in vitro restimulation with mesothelin-coated beads. Supplemental Figure 6. Densitometry analyses of signaling proteins. Supplemental Figure 7. Expression of PGE2 in our tumor cells and the effect of mesoCAR-RIAD T cells on tumors that do not express the antigen mesothelin. Supplemental Figure 8. Greater influx of CD4+ CAR T cells in human and murine tumors.</p>

Supplemental Figure Legends from Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors

2023-04-03

<p>Figure legends for supplemental data.</p>

Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors

Cell Reports Medicine · 2023-05-23 · 60 citations

Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malignancies, but their effectiveness in non-hematopoietic cancers remains limited. This study proposes enhancing CAR T cell function and localization in solid tumors by modifying the epigenome governing tissue-residency adaptation and early memory differentiation. We identify that a key factor in human tissue-resident memory CAR T cell (CAR-TRM) formation is activation in the presence of the pleotropic cytokine, transforming growth factor β (TGF-β), which enforces a core program of both “stemness” and sustained tissue residency by mediating chromatin remodeling and concurrent transcriptional changes. This approach leads to a practical and clinically actionable in vitro production method for engineering peripheral blood T cells into a large number of “stem-like” CAR-TRM cells resistant to tumor-associated dysfunction, possessing an enhanced ability to accumulate in situ and rapidly eliminate cancer cells for more effective immunotherapy.

Data from Function of Human Tumor-Infiltrating Lymphocytes in Early-Stage Non–Small Cell Lung Cancer

2023-04-04

<div>Abstract<p>Cancer progression is marked by dysfunctional tumor-infiltrating lymphocytes (TIL) with high inhibitory receptor (IR) expression. Because IR blockade has led to clinical responses in some patients with non–small cell lung cancer (NSCLC), we investigated how IRs influenced CD8<sup>+</sup> TIL function from freshly digested early-stage NSCLC tissues using a killing assay and intracellular cytokine staining after <i>in vitro</i> T-cell restimulation. Early-stage lung cancer TIL function was heterogeneous with only about one third of patients showing decrements in cytokine production and lytic function. TIL hypofunction did not correlate with clinical factors, coexisting immune cells (macrophages, neutrophils, or CD4<sup>+</sup> T regulatory cells), nor with PD-1, TIGIT, TIM-3, CD39, or CTLA-4 expression. Instead, we found that the presence of the integrin α<sub>e</sub>β<sub>7</sub> (CD103), characteristic of tissue-resident memory cells (T<sub>RM</sub>), was positively associated with cytokine production, whereas expression of the transcription factor Eomesodermin (Eomes) was negatively associated with TIL function. These data suggest that the functionality of CD8<sup>+</sup> TILs from early-stage NSCLCs may be influenced by competition between an antitumor CD103<sup>+</sup> T<sub>RM</sub> program and an exhaustion program marked by Eomes expression. Understanding the mechanisms of T-cell function in the progression of lung cancer may have clinical implications for immunotherapy.</p></div>