253 Anti-TIGIT antibodies require enhanced FcγR co-engagement for optimal T and NK cell-dependent anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A275-A275
Author(s):  
Rebecca Ward ◽  
Elena Paltrinieri ◽  
Marilyn Marques ◽  
Priyadarshini Iyer ◽  
Sylvia Dietrich ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Control ◽  
Tumor Bearing ◽  
Anti Tumor Activity ◽  
Ct26 Tumor ◽  
Dependent Mechanism

BackgroundT-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an important negative regulator of the immune response to cancer that contributes to resistance/relapse to anti-PD-1 therapy.1 In clinical trials, anti-human (h) TIGIT antibodies have shown promising activity in combination with anti-PD-1/PD-L1 antibodies for the treatment of various solid tumors.2 However, the optimal format for anti-TIGIT antibodies remains controversial. Here we describe a novel Fcγ receptor (FcγR)-dependent mechanism of action that is critical for enhancing T and NK cell anti-tumor immunity, and, further informs on the optimal design of anti-TIGIT antibodies.MethodsWe investigated a panel of Fc-silent, Fc-competent, and Fc-engineered anti-mouse (m) TIGIT antibody variants in syngeneic murine CT26 tumor-bearing or B16F10 pseudo-metastases models. To further elucidate the relative contribution of T and NK cells in controlling tumor growth, we assessed the activity of Fc-engineered anti-TIGIT antibodies in NK cell-depleted or T cell-deficient (Nu-Foxn1nu) CT26 tumor-bearing mice. Immune-related pharmacodynamic changes in the tumor microenvironment were assessed by flow cytometry. We further validated these findings in primary human T and NK cell activation assays using Fc-engineered anti-human TIGIT antibodies.ResultsThe Fc-engineered anti-mTIGIT antibody, which demonstrates enhanced binding to mouse FcγRIV, was the only variant to deliver single agent anti-tumor activity. The Fc-enhanced variant outperformed the Fc-competent variant while the Fc-inert variant had no anti-tumor activity. Tumor control by anti-mTIGIT antibodies was not dependent on Treg depletion, but rather on increased frequency of CD8+ T cells and activated NK cells (Ki67, IFNγ, CD107a and TRAIL) in the tumor microenvironment. Concordant with observations in the mouse, Fc-engineered anti-hTIGIT antibodies with improved binding to FcγRIIIA demonstrate superior T and NK cell activation in PBMC-based assays compared to a standard hIgG1 variant. Notably, superior activity of the Fc-engineered anti-hTIGIT antibody was observed from PBMC donors that express either high or low affinity FcγRIIIA. Blockade of FcγRIIIA or depletion of CD14+ and CD56+ cells reduced the functional activity of the Fc-enhanced anti-TIGIT antibody, confirming the requirement for FcγR co-engagement to maximize T cell responses.ConclusionsOur data demonstrate the importance of FcγR co-engagement by anti-TIGIT antibodies to promote immune activation and tumor control. First generation anti-TIGIT antibodies are not optimally designed to co-engage all FcγRIIIA variants. However, Fc-enhanced anti-TIGIT antibodies unlock a novel FcγR-dependent mechanism of action to enhance T and NK cell-dependent anti-tumor immunity and further improve therapeutic outcomes.ReferencesJohnston RJ, et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26:923–37.Rodriguez-Abreu D, et al., Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). Journal of Clinical Oncology 2020; 38:15_suppl, 9503–9503.

398 AGEN1181, an Fc engineered anti-CTLA-4 antibody, demonstrates clinical activity, alone or in combination with balstilimab (anti-PD-1), and broadens the therapeutic potential of CTLA-4 therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A423-A423
Author(s):  
Steven O’Day ◽  
Anthony El khoueiry ◽  
Chethan Ramamurthy ◽  
Andrea Bullock ◽  
Irina Shapiro ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Models ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Control ◽  
Clinical Activity ◽  
Small Subset ◽  
Tumor Bearing Mouse ◽  
High Affinity ◽  
Tumor Bearing

BackgroundImmune checkpoint therapies targeting CTLA-4, alone, or in combination with anti-PD-1 have shown durable responses in cancer patients. However, responses are limited to a small subset of patients in the most common immunogenic cancers. Here we describe, a novel anti-CTLA-4 antibody, AGEN1181, with enhanced FcyR-dependent functionality that harnesses a novel mechanism of action to promote superior T cell activation and anti-cancer immunity. Concordant with preclinical findings, we report preliminary safety, pharmacodynamic and efficacy data from a phase 1 study of AGEN1181 (NCT03860272), alone or in combination with balstilimab (anti-PD-1 antibody) in a range of immunogenic and non-immunogenic tumors.MethodsThe functional activity of AGEN1181 or AGEN1181-like mouse surrogate were assessed in primary cell-based assays or in PD-1 refractory syngeneic tumor-bearing mouse models (B16F10 or KPC pancreatic tumor). Efficacy was evaluated as monotherapy, or in combination with anti-PD-1, focal radiation or chemotherapy. In an ongoing phase I study, AGEN1181 is administered intravenously once every 3- or 6-weeks as monotherapy (0.1–4 mg/kg), or every 6-weeks (1–4 mg/kg) in combination with balstilimab (3 mg/kg) dosed every 2 weeks. Dose-limiting toxicities were evaluated in the first 28 days of treatment. Neoantigen burden was assessed from pre-treatment tumor biopsy, as available, by next-generation sequencing. Fcγ receptor genotyping was assessed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry.ResultsPreclinically, AGEN1181 demonstrated superior T cell activation than a standard IgG1 anti-CTLA-4 analogue in donors expressing either the low or high affinity FcγRIIIA. In poorly immunogenic tumor-bearing mouse models, AGEN1181-like surrogate demonstrated robust tumor control in combination with anti-PD-1 and focal radiation or chemotherapy. As of August 25th, 2020, we observed a clinical benefit rate of 63–53% at 6 and 12 weeks respectively among evaluable treated patients. We observed two durable responses in patients with endometrial cancer that were BRCA-, microsatellite stable and PD-L1 negative. These patients progressed on prior PD-1 therapy or chemoradiation respectively. Notably, responders expressed either the low or high affinity FcγRIIIA. AGEN1181 showed potent dose-dependent increases in peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T-cells. Treatment was well tolerated through the highest dose tested. Grade 3 or greater immune-related adverse events occurred in 28.5% patients and were consistent with CTLA-4 therapies.ConclusionsAGEN1181 is designed to expand the benefit of anti-CTLA-4 therapy to a broader patient population. AGEN1181, alone or in combination with balstilimab, demonstrates clinical activity in heavily pretreated patients.Trial RegistrationNCT03860272

scholarly journals Successful IL-12 cancer immunotherapy requires NK cell-derived CCL5 for anti-tumor DC-T cell crosstalk

2021 ◽  
Author(s):  
Nicole Kirchhammer ◽  
Marcel P Trefny ◽  
Marina Natoli ◽  
Dominik Bruecher ◽  
Sheena N Smith ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Feedback Mechanism ◽  
Tumor Control ◽  
Positive Feedback Mechanism ◽  
Cell Crosstalk

Targeting T cells for cancer immunotherapy commonly fails to generate lasting tumor control. Harnessing additional orchestrators of the immune response against tumors may enhance and broaden clinical benefit. Here, we demonstrate that therapeutic targeting of the IFNγ-IL-12 pathway relies on the amplification of anti-tumoral DC-T cell crosstalk by NK cells. Utilizing an engineered adenoviral platform for paracrine delivery into the tumor microenvironment, we show that IL-12 enhances functional DC-CD8 T cell interactions to generate profound anti-tumor immunity. This effect depends on the abundance of intra-tumoral NK cells and specifically their capacity to produce the DC chemoattractant CCL5. Failure to respond to IL-12 and other IFNγ-inducing therapies such as immune checkpoint blockade can be overcome by intra-tumoral therapeutic delivery of CCL5 resulting in the recruitment of cDC1s. Our findings reveal novel mechanistic insights how to enhance T cell-NK cell-DC crosstalks, enforcing a tumor-eliminating positive feedback mechanism to promote anti-tumor immunity and overcome resistance.

scholarly journals NK cells mediate clearance of CD8+ T cell–resistant tumors in response to STING agonists

2020 ◽  
Vol 5 (45) ◽  
pp. eaaz2738 ◽  
Author(s):  
Christopher J. Nicolai ◽  
Natalie Wolf ◽  
I-Chang Chang ◽  
Georgia Kirn ◽  
Assaf Marcus ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Tumor Control ◽  
Type I ◽  
Dependent Manner ◽  
Tumor Models

Several immunotherapy approaches that mobilize CD8+ T cell responses stimulate tumor rejection, and some, such as checkpoint blockade, have been approved for several cancer indications and show impressive increases in patient survival. However, tumors may evade CD8+ T cell recognition via loss of MHC molecules or because they contain few or no neoantigens. Therefore, approaches are needed to combat CD8+ T cell–resistant cancers. STING-activating cyclic dinucleotides (CDNs) are a new class of immune-stimulating agents that elicit impressive CD8+ T cell–mediated tumor rejection in preclinical tumor models and are now being tested in clinical trials. Here, we demonstrate powerful CDN-induced, natural killer (NK) cell–mediated tumor rejection in numerous tumor models, independent of CD8+ T cells. CDNs enhanced NK cell activation, cytotoxicity, and antitumor effects in part by inducing type I interferon (IFN). IFN acted in part directly on NK cells in vivo and in part indirectly via the induction of IL-15 and IL-15 receptors, which were important for CDN-induced NK activation and tumor control. After in vivo administration of CDNs, dendritic cells (DCs) up-regulated IL-15Rα in an IFN-dependent manner. Mice lacking the type I IFN receptor specifically on DCs had reduced NK cell activation and tumor control. Therapeutics that activate NK cells, such as CDNs, checkpoint inhibitors, NK cell engagers, and cytokines, may represent next-generation approaches to cancer immunotherapy.

scholarly journals 692 Tim-3 expression drives phenotypic and functional changes in Treg in secondary lymphoid organs and the tumor microenvironment, effecting tumor burden

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A720-A720
Author(s):  
Hridesh Banerjee ◽  
Hector Nieves-Rosado ◽  
Benjamin Murter ◽  
Lawrence Kane
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Burden ◽  
Lymphoid Organs ◽  
Functional Changes ◽  
The Impact

BackgroundRegulatory T cells (T reg) are critical mediators of self-tolerance but can also limit effective anti-tumor immunity. We and others previously reported that 40–60% percent of T reg-infiltrating head and neck cancer (HNC) and other tumors highly express Tim-3, compared with about 5% in lymphoid organs, it therefore gets imperative to characterize if Tim-3 is driving any T reg specific function in tumor microenvironment and under homeostasis.MethodsUsing a conditional TIM-3 inducible and knockout mouse model developed in our lab, we have performed syngeneic tumor challenges in T reg-specific Tim-3 transgenic and knockout mice (FoxP3ERT2CreSFS-Tim-3 and FoxP3ERT2Cre-FLEX4). We have also characterized the tumor immune infiltrate of these mice to understand the impact of T reg specific Tim-3induction and deficiency on the immune landscape.ResultsTim-3 induction on T reg leads to rapid growth associated with higher progression of CD8 compartment towards exhaustion, while TIm-3 knockout in T reg specific manner leads top overall decline in T reg compartment in tumors associated with lower exhaustion in the CD8 compartment and decrease in tumor burden,ConclusionsTumor-infiltrating Tim-3+ Treg have enhanced suppressive function and display a more effector-like phenotype. Using a novel mouse model with cell type-specific Tim-3 expression, we show here that expression of Tim-3 by Treg is sufficient to drive Treg to a more effector-like phenotype, and increases suppressive activity, effector T cell exhaustion and tumor growth. We also show that inducible deletion of Tim-3 specifically from Treg enhances anti-tumor immunity and decrease in tumor burden along with a decrease in tumor associated Treg compartment. These findings may help to reconcile previous reports that some Tim-3 antibodies enhance T cell responses in vivo, while expression of Tim-3 has a cell-intrinsic ability to enhance TCR signaling and T cell activation. A major role of Tim-3 was found to be mediated through IL-10 and IL-10 R pathway in both Treg and CD8 compartment. Thus, we propose that Tim-3 regulates anti-tumor immunity at least in part through enhancement of Treg function. To our knowledge, this is the first example in which expression of a single co-stimulatory molecule is sufficient to drive differentiation of Treg in this manner.AcknowledgementsWe acknoledge Dr. Robert L. Ferris and Dr. Greg M. Delgoffe for their inputs and guidance with human and metabolism associated experiments.

188 Novel Anti-SIRpalpha antibodies with differentiated characteristics as promising cancer therapeutics

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A202-A202
Author(s):  
Swati Jalgaonkar ◽  
George Huang ◽  
Erin Filbert ◽  
Christine Tan ◽  
Ryan Alvarado ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Immunity ◽  
Cell Activation ◽  
Regulatory Protein ◽  
Cancer Therapeutics ◽  
Myeloid Cell ◽  
Therapeutic Window ◽  
Close Relative ◽  
Cell Functions ◽  
Tumor Clearance

BackgroundTherapeutically targeting tumor myeloid cells has emerged as a novel and complementary strategy to existing cancer immunotherapy approaches. The interaction of tumor expressed CD47 with SIRP alpha (signal regulatory protein-alphaa, SIRPA) on macrophages, dendritic cells and neutrophils inhibits key immune effector mechanisms. Targeting SIRPa-CD47 represents a novel approach to enhance anti-tumor immunity by augmenting or reactivating critical tumor clearance mechanisms.H5F9, an antibody against CD47, has shown promising therapeutic activities in patients with MSD, AML and NHL. However, agents targeting CD47 present hematological toxicities and present a huge antigen sink leading to not achieving an optimum therapeutic window. Our approach is to target SIRP alpha, the receptor of CD47 and focus therapeutic targeting to relevant mechanisms related to phagocytosis and myeloid cell activation and at the same time avoid undesired effects of blocking CD47. SIRP gamma, a very close relative of SIRP alpha is expressed on T cells and also binds to CD47. It has been shown that blockade of SIRP gamma-CD47 interaction inhibits T cell proliferation and blocks trans-endothelial T cell migration. Hence, our aim is to generate SIRP alpha selective antibodies that do not cross-react with SIRP gamma and have minimal impact on T cell functions.MethodsUsing Apexigen’s APXiMAB™ proprietary antibody discovery platform, we have generated two novel anti-SIRP alpha antibodies (APX701 & APX702) with differentiated properties as compared to other approaches targeting the CD47/SIRP alpha axis. We have used ELISA, FACS based cell binding and blocking assays, and functional assays including in vitro phagocytosis and antibody-dependent cell phagocytosis (ADCP) in combination with tumor-opsonizing antibody to select APX701 & APX702.ResultsOur novel preclinical-stage APX701 & APX702 antibodies have demonstrated the following attributes: high binding affinity to human SIRP alpha (APX701 Kd = 0.95nM, APX702 Kd = 0.88nM), no binding to SIRP gamma, efficient blockade of SIRP alpha binding to CD47(APX701 IC50 = 1.04nM, APX702 IC50 = 0.80nM), potent macrophage mediated phagocytosis, enhancement of ADCP mediated by tumor-opsonizing antibody and favorable developability CMC profiles. In comparison with the benchmark antibody OSE-172, APX701 & APX702 showed potent phagocytosis activity and ADCP enhancement in all donors tested while OSE-172 induced phagocytosis in only 50% of the donors. This may result from the fact that APX701 and APX702 bind to all major SIRP alpha variants (V1, V2 & V8; covering ~92% population) while OSE 172 only binds to SIRPalpha V1 (~50% population).ConclusionsAPX701 and APX702 demonstrate differentiated anti-SIRPalpha activities by enhancing myeloid cell-mediated anti-tumor immunity and reactivating critical tumor clearance mechanisms within the tumor microenvironment.

scholarly journals PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emily Lee ◽  
Sarah Szvetecz ◽  
Ryan Polli ◽  
Angelo Grauel ◽  
Jayson Chen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
High Grade ◽  
Ovarian Cancers ◽  
Late Stage Diagnosis ◽  
Anti Tumor Activity

AbstractHigh-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

scholarly journals 678 Addition of a single bacteria facilitates anti-tumor immunity and long-term survival in colorectal cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A717-A717
Author(s):  
Abigail Overacre-Delgoffe ◽  
Anthony Cillo ◽  
Hannah Bumgarner ◽  
Ansen Burr ◽  
Justin Tometich ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Tumor Immunity ◽  
Tumor Burden ◽  
Intestinal Microbiome ◽  
Tumor Control ◽  
Mesenteric Lymph Nodes ◽  
Term Survival ◽  
16S Sequencing ◽  
Tumor Bearing

BackgroundColorectal cancer remains one of the most common and deadliest cancers worldwide and effective therapies are lacking. While immunotherapy has revolutionized treatment for many cancers, the overwhelming majority of colorectal cancer patients are non-responsive and the 5-year survival rate for advanced disease is <20%. Immunotherapeutic response has been associated with select members of the microbiome in melanoma; however, the potential benefit in colorectal cancer and the underlying mechanisms remain unclear. We sought to determine how specific members of the intestinal microbiome affect anti-tumor immunity in colorectal cancer (CRC) in hopes of discovering novel treatments and revealing potential hurdles to current therapeutic response in CRC patients.MethodsWe utilized a carcinogen-induced mouse model of CRC and colonized half of the tumor-bearing mice with Helicobacter hepaticus (Hhep) 7 weeks post AOM. Tumor number was assessed 12 weeks post AOM. We isolated lymphocytes from the lamina propria, colonic epithelium, mesenteric lymph nodes, and tumor(s) to track the spatial and transcriptional Hhep-specific and endogenous immune responses during tumor progression through 5’ single cell RNAseq, flow cytometry, and immunofluorescence. In addition, we utilized 16S sequencing and FISH to track Hhep colonization, location within the colon, and its impact on the surrounding microbiome.ResultsWe have found that rational modification of the microbiome of colon tumor-bearing mice through addition of a single bacteria, Hhep, led to tumor control or clearance and a significant survival advantage. Colonization led to the expansion of the lymphatic network and development of numerous peri- or intra-tumoral tertiary lymphoid structures (TLS) composed of Hhep-specific CD4 T follicular helper cells (TFH) as well as the bacteria itself. This led to an overall ‘heating’ of the tumor, wherein we saw an increase of CD4 T cell infiltration to the tumor core as well as an increase in CD103+ type 1 DC (cDC1) recruitment through increased chemokines such as CCL5 and XCL1. Hhep-specific TFH were both necessary and sufficient to drive TLS formation, increased immune invasion, and anti-tumor immunity.ConclusionsWe have shown that addition of a single bacteria, Hhep, leads to a reduction in CRC tumor burden or clearance through lymphatic expansion, TLS formation, and remodeling of the tumor microenvironment, and that Hhep-specific T cells are required for tumor control. These studies suggest that rational modification of the microbiome and microbiome-specific T cells can positively impact anti-tumor immunity and may represent a unique immunotherapeutic target to turn resistant tumors into responsive tumors.

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

scholarly journals DCision-making in tumors governs T cell anti-tumor immunity

Oncogene ◽  
2021 ◽  
Author(s):  
Francesca Alfei ◽  
Ping-Chih Ho ◽  
Wan-Lin Lo
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Cancer Treatment ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Oncological Treatment

AbstractThe exploitation of T cell-based immunotherapies and immune checkpoint blockade for cancer treatment has dramatically shifted oncological treatment paradigms and broadened the horizons of cancer immunology. Dendritic cells have emerged as the critical tailors of T cell immune responses, which initiate and coordinate anti-tumor immunity. Importantly, genetic alterations in cancer cells, cytokines and chemokines produced by cancer and stromal cells, and the process of tumor microenvironmental regulation can compromise dendritic cell–T cell cross-talk, thereby disrupting anti-tumor T cell responses. This review summarizes how T cell activation is controlled by dendritic cells and how the tumor microenvironment alters dendritic cell properties in the context of the anti-tumor immune cycle. Furthermore, we will highlight therapeutic options for tailoring dendritic cell-mediated decision-making in T cells for cancer treatment.

158 Inhibition of PI3Kδ improves tumor specific T cell immunity and metabolic fitness

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A172-A172
Author(s):  
Guillermo Rangel Rivera ◽  
Guillermo Rangel RIvera ◽  
Connor Dwyer ◽  
Dimitrios Arhontoulis ◽  
Hannah Knochelmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Immunity ◽  
Mitochondrial Function ◽  
T Cell Differentiation ◽  
Tumor Control ◽  
T Cell Therapy

BackgroundDurable responses have been observed with adoptive T cell therapy (ACT) in some patients. However, current protocols used to expand T cells often exhibit suboptimal tumor control. Failure in these therapies has been attributed to premature differentiation and impaired metabolism of the infused T cells. Previous work done in our lab showed that reduced PI3Kδ signaling improved ACT. Because PI3Kγ and PI3Kδ have critical regulatory roles in T cell differentiation and function, we tested whether inhibiting PI3Kγ could recapitulate or synergize PI3Kδ blockade.MethodsTo test this, we primed melanoma specific CD8+ pmel-1 T cells, which are specific to the glycoprotein 100 epitope, in the presence of PI3Kγ (IPI-459), PI3Kδ (CAL101 or TGR-1202) or PI3Kγ/δ (IPI-145) inhibitors following antigen stimulation with hgp100, and then infused them into 5Gy total body irradiated B16F10 tumor bearing mice. We characterized the phenotype of the transferred product by flow cytometry and then assessed their tumor control by measuring the tumor area every other day with clippers. For metabolic assays we utilized the 2-NBDG glucose uptake dye and the real time energy flux analysis by seahorse.ResultsSole inhibition of PI3Kδ or PI3Kγ in vitro promoted greater tumor immunity and survival compared to dual inhibition. To understand how PI3Kδ or PI3Kγ blockade improved T cell therapy, we assessed their phenotype. CAL101 treatment produced more CD62LhiCD44lo T cells compared to IPI-459, while TGR-1202 enriched mostly CD62LhiCD44hi T cells. Because decreased T cell differentiation is associated with mitochondrial metabolism, we focused on CAL101 treated T cells to study their metabolism. We found that CAL101 decreased glucose uptake and increased mitochondrial respiration in vitro, indicating augmented mitochondrial function.ConclusionsThese findings indicate that blocking PI3Kδ is sufficient to mediate lasting tumor immunity of adoptively transferred T cells by preventing premature differentiation and improving mitochondrial fitness. Our data suggest that addition of CAL101 to ACT expansion protocols could greatly improve T cell therapies for solid tumors by preventing T cell differentiation and improving mitochondrial function.

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