The Sentinel


Saturday, November 13, 2021

SITC AMPCP 2021 Scientific Highlights – Friday 11/12/21

Engineered myeloid cells make the microenvironment more favorable 

209 Genetically Engineered Myeloid Cells (GEMys) as a Platform to Enhance Antitumor Immunity 

Sabina Kaczanowska, PhD (National Cancer Institute) presented evidence that engineered IL-12-expressing myeloid cells home to tumors and modulate effector cell functions in the microenvironment. Previous work by this group has demonstrated that bone marrow-derived myeloid cells play a central role in establishing the pre-metastatic niche. In murine models of lung metastases, treatment with IL-12-expressing myeloid cells was associated with robust interferon gamma responses, elevated antigen presentation machinery, and high infiltrating T and NK cells expressing effector markers. Tumor growth was blunted in mice infused with engineered cells, resulting in fewer metastases, and prolonged survival compared to controls. When combined with chemotherapy pre-conditioning, treatment not only was associated with complete rejection of established tumors but also resistance to rechallenge. Translation of these findings into human patients could open the door for myeloid-targeting strategies to prevent metastasis in advanced cancer.


Combination improves survival for immunologically cold endometrial cancer 

(354) Lenvatinib and pembrolizumab in advanced endometrial carcinoma (EC): long-term efficacy and safety update from a phase 1b/2 study

Vicky Makker, MD (Memorial-Sloan Kettering Cancer Center) delivered an update from a phase Ib/II study of the multikinase inhibitor lenvatinib plus the pembrolizumab for metastatic, pre-treated endometrial carcinoma. The trial enrolled  108 patients, 94 of whom had confirmed microsatellite stable (MSS)/mismatch repair proficient (pMMR) disease and 11 with documented microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) tumors. At data cutoff on January 10, 2019 with a median follow-up of 18.7 months, the objective response rate (ORR) was 38.9%, median progression-free survival (PFS) was 7.4 months, and median overall survival (OS) was 16.7 months. Now, with a median follow up of 34.7 months, the updated ORR is 38.3% (including an 8.3% complete response rate) and 63.6% for MSHI-H/dMMR tumors. Median PFS remained consistent with the first analysis at 7.4 months (7.4 and 26.4 months for MSS/pMMR and MSI-H/dMMR tumors, respectively), and the updated median OS is 17.7 months (17.2 months and not reached for MSS/pMMR and MSI-H/dMMR tumors, respectively). No new safety signals were detected. With continued follow-up, this phase Ib/II study that included primarily patients with MSS/pMMR advanced endometrial carcinoma continues to demonstrate efficacy not previously achieved with pembrolizumab monotherapy in this “immunologically cold” tumor. A phase III trial of lenvatinib plus pembrolizumab compared to chemotherapy is ongoing.


Novel drug traffics non-conventional T to cells tumors

(503) Clinical Activity of ICT01, an anti-BTN3A-Targeted, γ9δ2-Activating mAb, Alone and in Combination with Pembrolizumab in Patients with Advanced/Refractory Solid Tumors: EVICTION Trial

Martin Wermke, MD (Technical University, Dresden) described clinical evidence that treatment with an antibody targeting butyrophilin-3A (ICT01) leads to tumor infiltration by the non-conventional cytotoxic γ9δ2 T cell subset.  In the ongoing phase I/IIa EVICTION trial, dose-escalation of ICT01 (20µg to 200mg) has been completed as well as three dose cohorts of ICT01 (700µg, 2mg, or 7 mg) plus pembrolizumab. Blood samples were collected and tumors were biopsied for analysis at baseline and on day 28. No dose-limiting toxicities were observed in any of the completed cohorts. Treatment mediated  trafficking of γ9δ2 T cells out of circulation with, associated intra-tumoral increases in total γδ (3 to 34-fold), CD3+ (3 to 55-fold) and CD8+ T cells (1.3 to 66-fold). Stable disease as measured by RECISTv1.1 was observed in 6 of 19 evaluable patients in the dose-escalation cohort and 5 of 8 evaluable patients in the combination cohort. Furthermore, 2 of 8 patients in the combination cohort had a PR. One patient notably had shrinkage of an intracranial metastatic melanoma lesion in a patient refractory to prior ipilimumab plus nivolumab after initial pseudoprogression. These preliminary data suggest that ICT01 effectively mobilizes γ9δ2 T cells to tumors and clinical benefit may be enhanced when combined with pembrolizumab.


Autoantigen driving immune-related myocarditis identified

(805) Clonal, activated CD8+ T cells recognizing cardiac alpha-myosin drive immune checkpoint inhibitor associated myocarditis in mice

Margaret Axelrod, BS (Vanderbilt University) presented a new murine model of checkpoint inhibitor-induced myocarditis that led to the identification cardiac alpha-myosin as a key autoantigen driving this rare but often deadly toxicity. Mice with homozygous knockouts of the gene encoding PD-1 and heterozygous deletion of the CTLA-4 encoding locus spontaneously develop fatal myocarditis that recapitulates the clinical features of human immune-mediated toxicity. Depletion of either CD4+ or CD8+ T cells rescued survival in mice, but single cell RNA/T cell receptor sequencing identified CD8+ T cells as the dominant population in the cardiac immune infiltrate. Reporter assays confirmed that the most clonally expanded receptors recognized epitopes of alpha-myosin. This study is the first identification of a candidate autoantigen in checkpoint blockade-associated-myocarditis and efforts are underway to determine if human T cell receptors isolated and sequenced from patient samples also recognize similar epitopes.


Gut microbiota contribute  to colorectal cancer immune contexture

(839) Microbiota-specific T follicular helper cells drive tertiary lymphoid structure formation and anti-tumor immunity in colorectal cancer

Abigail Overacre-Delgoffe, PhD (University of Pittsburgh) discovered  that T cells specific to individual constituents of the gut microbiota are involved in anti-tumor immunity. In a carcinogen-induced model of colorectal cancer, mice colonized by the enterohepatic pathogen Helicobacter hepaticus was associated with decreased tumor burden and prolonged survival compared to uncolonized controls. Tumors isolated from H. hepaticus-colonized animals displayed mature peri- or intra-tumoral tertiary lymphoid structures, which were associated with high levels of infiltration of cytotoxic T and NK cells. Depletion of CD8+ T cells did not attenuate the anti-tumor effects of colonization with H. hepaticus, however, CD4+ T follicular helper cells were necessary and sufficient to slow tumor growth. These data reveal unappreciated roles for the microbiota as well as CD4+ T follicular helper cells in modulating the tumor immune microenvironment, possibly paving the way toward new therapeutic targets.


Sex differences shape the tumor microenvironment in pancreatic cancer

(885) Targeting FPR2 as a novel approach for immunotherapy in pancreatic cancer female patients – Studies of sexual immune dimorphism in the tumor microenvironment

Dhifaf Sarhan, PhD (Karolinska Institutet) identified a sex-specific mechanism of myeloid-cell driven immune exhaustion that contributes to the immunologically cold phenotype of pancreatic cancer. Interrogation of murine and human transcriptomic data showed elevated expression of G-coupled protein receptor formyl peptide receptor 2 (FPR2) in pancreatic tumor samples compared to healthy tissues. FPR2 was also higher in women than in men. FPR2-expressing myeloid cells in tumors were associated with distinct sex-specific immunophenotypes for both mice and humans, with an immune-excluded phenotype predominating in females versus an immune-ignored phenotype in males. In vitro, myeloid cells treated with FPR2 agonist induced TIM3 and PD-1 on T cells isolated from women but not from men. Knockout of FPR2 slowed subcutaneously injected pancreatic tumor growth to a significantly greater extent in female mice compared to males. Data from human patients with pancreatic cancer and other gastric malignancies confirmed an association between FRP2 expression and poor survival outcomes in women only. This study opens the door to sex-specific personalized immunotherapy approaches and reveals myeloid FPR2 as a new microenvironmental mediator involved in T cell exhaustion in women.


First human experience with CAR-transduced macrophages reported

(951) A Phase 1 first in human study of adenovirally transduced anti-HER2 CAR Macrophages in subjects with HER2 overexpressing solid tumors: preliminary safety, pharmacokinetics, and TME reprogramming data

Kim Reiss, MD (University of Pennsylvania) reported the first-in-human experience with adoptive therapy with CAR-transduced macrophages. To date, two patients have been treated with CT-0508, an autologous adoptive cell therapy consisting of monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. For manufacturing, patients received four doses of filgrastim for monocyte mobilization prior to apheresis and adenoviral delivery of an anti-HER2 CAR. Treatment was well-tolerated, with no dose-limiting toxicities and no therapy-related toxicities of grade 4 or greater. One participant developed grade 2 CRS three days post-infusion, which resolved on the same day. Transcriptomic analysis of tumor tissue samples revealed rapid recruitment of inflammatory innate immune and naïve T cells by 8 days after infusion. By the 4-week timepoint, significant infiltration by activated and proliferating CD8+ T cells were observed. The trial is continuing to recruit patients, and the data thus far continue to indicate that CT-0508 elicits favorable changes in the tumors.

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