scholarly journals 12 Key pharmacokinetic and pharmacodynamic parameters that correlate with the anti-tumor activity of a bispecific PD-L1 conditional 4–1BB agonist

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A12-A12
Author(s):  
Heather Kinkead ◽  
Chelsie Macedo ◽  
Angelica Sanabria ◽  
Garrett Cyprus ◽  
Rajay Pandit ◽  
...  
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Receptor Occupancy ◽  
Effector Memory ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Human Trial ◽  
Tumor Bearing ◽  
Link Type

Background4-1BB is a costimulatory molecule that is predominantly expressed on activated CD8+ T cells and is induced upon T cell receptor mediated activation.1 Within the tumor microenvironment, 4-1BB-expressing T cells are enriched for anti-tumor reactivity 2; thus, 4-1BB agonism provides an opportunity for selective activation of anti-cancer immune effector cells. Early efforts to develop 4-1BB targeted agonists were limited by poor tolerability (Urelumab) or insufficient efficacy (Utomilumab). INBRX-105 is a bispecific antibody that aims to overcome these prior limitations through induction of 4-1BB agonism specifically at sites of PD-L1 expression. Preclinical models have defined pharmacokinetic (PK) and pharmacodynamic (PD) parameters that are correlated with maximal INBRX-105-specific immune responses and antitumor activity.MethodsINBRX-105 was generated by linking 2 humanized single-domain antibody binding domains targeting human PD-L1 and 4-1BB, fused to an effector-silenced human IgG1 constant domain (Fc). A bispecific, anti-mouse PD-L1x4-1BB surrogate molecule, INBRX-105-a, was engineered to match the function and target affinities of INBRX-105. This surrogate was tested for in vivo activity in non-tumor-bearing and MC-38 tumor-bearing animals, including measurements of serum exposure, PD-L1 receptor occupancy, immunophenotyping of peripheral blood and intra-tumoral immune cell populations.ResultsINBRX-105-a was shown to be an appropriate anti-mouse surrogate for INBRX-105 in a variety of in vitro assays. Comparable potencies of activity were demonstrated in a PD-L1 dependent 4-1BB reporter assay, as well as in cytokine induction through co-stimulation of primary T cells. In vivo, INBRX-105-a showed robust induction of mouse CD8+ T effector memory populations (CD8+ TEM) at dose levels that achieved ≥ 96 hours of PD-L1 receptor occupancy. A serum concentration of 800 ng/mL at 96 hours, achieved by a dose of 2 mg/kg in mice, was sufficient to provide the requisite occupancy for maximal pharmacodynamics. CD8+ TEM responses were dependent on 4-1BB agonism and were more efficiently induced by PD-L1 localization, as opposed to 4-1BB multivalent clustering alone. Optimal tumor responses, including complete responses and demonstration of immunological memory, were observed when maximal 4-1BB driven pharmacodynamics were paired with extended PD-1/PD-L1 pathway blockade, provided either by an orthogonal molecule or increased exposure of INBRX-105.ConclusionsPreclinical receptor occupancy and pharmacokinetic determinations have defined a dose of INBRX-105-like activity that induces maximal pharmacodynamics. Additional PD-1 checkpoint inhibition does not change the pharmacodynamic profile of INBRX-105-a, but does allow for optimal efficacy. INBRX-105 is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03809624).Trial RegistrationINBRX-105 is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03809624).ReferencesVinay DS, Kwon BS. 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB Reports; 2014:47:122–129.Ye Q, Song D-G, Poussin M, et al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res; 2014:20:44–55.Ethics ApprovalThe care and use of all animals were reviewed and approved by Explora BioLabs’ IACUC # SP17-010-013 and conducted in accordance with AAALAC regulations.

347 Clinical outcomes of ovarian cancer patients treated with ALKS 4230, a novel engineered cytokine, in combination with pembrolizumab: ARTISTRY-1 trial

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A372-A373
Author(s):  
Ira Winer ◽  
Lucy Gilbert ◽  
Ulka Vaishampayan ◽  
Seth Rosen ◽  
Christopher Hoimes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Marker ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Comprehensive Cancer Center ◽  
List Type ◽  
Link Type ◽  
Heavily Pretreated

BackgroundALKS 4230 is a novel engineered cytokine that selectively targets the intermediate-affinity interleukin-2 receptor complex to activate CD8+ T cells and natural killer cells.1 The ARTISTRY-1 trial (NCT02799095) has shown encouraging efficacy and acceptable tolerability of ALKS 4230 among patients with advanced solid tumors.2 We report a detailed analysis of ovarian cancer (OC) patients who received combination therapy in ARTISTRY-1.MethodsARTISTRY-1 is an ongoing multicohort phase 1/2 trial exploring intravenous ALKS 4230 as monotherapy and combined with pembrolizumab. OC patients were enrolled into a cohort with mixed anti PD 1/L1 unapproved tumor types who had progressed on prior chemotherapy. OC patients received ALKS 4230 (3 µg/kg) on days 1–5 and pembrolizumab (200 mg) on day 1 of a 21 day cycle. Outcomes presented include antitumor activity (RECIST v1.1) and safety as of 7/24/2020. To evaluate changes in tumor microenvironment (TME), baseline and on-treatment biopsies were collected.ResultsFourteen heavily pretreated patients with OC were enrolled. Patients received a median of 5 (range, 2 11) prior regimens and all were previously treated with platinum based therapy. Among 13 evaluable patients with ≥1 assessment, 9 experienced disease control and 4 experienced disease progression; median treatment duration was approximately 7 weeks. Three patients experienced an objective response, including 1 complete response, 1 partial response (PR), and 1 unconfirmed PR; all were platinum resistant and negative for BRCA mutations. Five patients experienced tumor burden reductions (table 1). Treatment-related adverse events at the doses tested have generally been transient and manageable, with the majority being grade 1 and 2 in severity. Overall, based on preliminary data, the combination with ALKS 4230 did not demonstrate any additive toxicity to that already established with pembrolizumab alone. Additional safety and efficacy data are being collected in ongoing cohorts. In the monotherapy dose escalation portion of the study, ALKS 4230 alone increased markers of lymphocyte infiltration in 1 paired melanoma biopsy (1 of 1; on treatment at cycle 2); CD8+ T cell density and PD-L1 tumor proportion score increased 5.2- and 11 fold, respectively, supporting evidence that ALKS 4230 has immunostimulatory impact on the TME and providing rationale for combining ALKS 4230 with pembrolizumab (figure 1).Abstract 347 Table 1Summary of response observations among patients with ovarian cancerAbstract 347 Figure 1Increased markers of lymphocyte tumor infiltrationAn increase in CD3+CD8+ T cells (A, red = CD3; blue = CD8; purple = CD3+CD8+; teal = tumor marker), GranzymeB (B, red = CD8; green = granzymeB; yellow = granzymeB+CD8+; teal = tumor marker), and PD-L1 (C, red = PD-L1; blue = tumor marker) in the tumor microenvironment of a single patient was observed after the patient received monotherapy ALKS 4230ConclusionsThe combination of ALKS 4230, an investigational agent, and pembrolizumab demonstrates an acceptable safety profile and provides some evidence of tumor shrinkage and disease stabilization in some patients with heavily pretreated OC. This regimen could represent a new therapeutic option for these patients.AcknowledgementsThe authors would like to thank all of the patients who are participating in this trial and their families. The trial is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel and funded by Alkermes, Inc.Trial RegistrationClinicalTrials. gov NCT02799095Ethics ApprovalThis trial was approved by Ethics and Institutional Review Boards (IRBs) at all trial sites; IRB reference numbers 16–229 (Dana-Farber Cancer Institute), MOD00003422/PH285316 (Roswell Park Comprehensive Cancer Center), 20160175 (Western IRB), i15-01394_MOD23 (New York University School of Medicine), TRIAL20190090 (Cleveland Clinic), and 0000097 (ADVARRA).ReferencesLopes JE, Fisher JL, Flick HL, Wang C, Sun L, Ernstoff MS, et al. ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy. J Immunother Cancer 2020;8:e000673. doi: 10.1136/jitc-2020-000673.Vaishampayan UN, Muzaffar J, Velcheti V, Winer I, Hoimes CJ, Rosen SD, et al. ALKS 4230 monotherapy and in combination with pembrolizumab (pembro) in patients (pts) with refractory solid tumors (ARTISTRY-1). Oral presentation at: European Society for Medical Oncology Annual Meeting; September 2020; virtual.

scholarly journals 412 First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A437-A437
Author(s):  
Elena Garralda ◽  
Ravit Geva ◽  
Eytan Ben-Ami ◽  
Corinne Maurice-Dror ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Dose Levels

BackgroundAgonistic 4-1BB monoclonal antibodies were preclinically validated as promising cancer immunotherapies, both as monotherapy and as potentiators of the activity of PD-(L)1–blocking agents. However, toxicity and a narrow therapeutic window have hampered their clinical development. DuoBody-PD­-L1×4-1BB, a first-in-class, bispecific, next-generation checkpoint immunotherapy, was designed to overcome these limitations by activating T cells through conditional 4-1BB costimulation, while simultaneously blocking the PD-L1 axis. We present preliminary data from the ongoing, first-in-human, open-label, phase I/IIa trial of DuoBody-PD-L1×4-1BB in advanced solid tumors (NCT03917381).MethodsDuring dose escalation, patients with metastatic or unresectable solid tumors not eligible for standard therapy received flat-dose DuoBody-PD-L1×4-1BB (25–1200 mg) intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included pharmacokinetic parameters and antitumor activity (RECIST 1.1). Pharmacodynamic biomarkers and antitumor activity (iRECIST) were assessed as exploratory endpoints.ResultsAs of June 22, 2020, 61 patients were enrolled (median age: 59 years). The most common cancer types were colorectal (19.7%), ovarian (14.8%), pancreatic (9.8%), and NSCLC (9.8%). Patients had previously received a median (range) of 3 (1–11) treatments; 44.2% had prior anti-PD-(L)1 immunotherapy. Patients received a median (range) of 4 (1–15) treatment cycles; Cmax was observed shortly after the end of infusion (mean T½: 2.3–10.3 days). Maximum tolerated dose was not reached; 6 patients experienced DLTs. The most common (=10%) treatment-related AEs (all grades; grades 3–4) were transaminase elevation (24.6%; 9.8%), hypothyroidism (16.4%; 1.6%), and fatigue (13.1%; 1.6%). Treatment-related grade-3 transaminase elevations decreased upon corticosteroid administration; no treatment-related bilirubin increases or grade-4 transaminase elevations occurred. Disease control, including stable disease at first assessment and partial responses in triple-negative breast cancer, ovarian cancer, and immune checkpoint inhibitor (ICI)–pretreated NSCLC, occurred in 40/61 patients (65.6%). Pharmacologic activity, as measured by modulation of adaptive immunity mediators, was observed across a broad range of dose levels. Peripheral proliferating (Ki67+) CD8+ effector memory T cells and serum interferon-gamma levels showed maximum induction relative to baseline (p=0.01) 8 days following treatment.ConclusionsDuoBody-PD-L1×4-1BB demonstrated biologic activity and a manageable safety profile. Encouraging early clinical activity across different dose levels was observed in a heavily pretreated population with advanced solid tumors, including those resistant to prior immunotherapy or typically less sensitive to ICIs. Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.AcknowledgementsThe authors thank Manish Gupta, Lei Pang, and Thomas Breuer at Genmab A/S; Alice Bexon, Alexander Muik, and Friederike Gieseke at BioNTech SE; and Zuzana Jirakova (formerly at BioNTech SE) for their valuable contributions. This trial was funded by Genmab A/S and BioNTech SE.Trial RegistrationClinicalTrials. gov; trial number: NCT03917381Ethics ApprovalThis trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board.ConsentWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

A phase I study to evaluate the T-cell engager AMV564 alone and in combination with pembrolizumab in subjects with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Alexander Starodub ◽  
Sarina Anne Piha-Paul ◽  
Raghad Karim ◽  
Curtis Ruegg ◽  
Victoria Smith ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gastroesophageal Junction ◽  
Effector Memory ◽  
Cytotoxic T Cell ◽  
Advanced Solid Tumors

3101 Background: Overcoming the immune-suppressive tumor environment induced by myeloid-derived suppressor cells (MDSC) is a major challenge in immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immune-suppressive factors. AMV564 is a bivalent, bispecific T-cell engager that binds CD3 and CD33. Preferential binding of AMV564 to areas of high CD33 density enables selective targeting of MDSC. Ex vivo data (Cheng 2017; Blood;130:51) and an ongoing clinical trial in acute myeloid leukemia (NCT03144245) demonstrate the ability of AMV564 to deplete MDSC while sparing monocytes and neutrophils. Methods: In this 3+3 dose escalation study, patients with advanced solid tumors receive AMV564 once daily via subcutaneous (SC) injection for 2 out of 3 wks per cycle, alone or in combination with pembrolizumab (200 mg every 3 wks). Key objectives are to evaluate AMV564 safety, identify a maximum tolerated or recommended phase 2 dose, and evaluate PK, immunophenotype of myeloid and T cell compartments, and preliminary efficacy. Results: Eleven patients have been enrolled: 8 monotherapy (3 at 15 mcg/d, 5 at 50 mcg/d) and 3 combination (5 mcg/d). Tumor types include ovarian (n = 2), small bowel, gastroesophageal junction, endometrial, rectal, penile, urothelial, squamous cell carcinoma (skin), appendiceal, and non-small cell lung. AMV564 was associated with grade (G) 1-2 injection site reactions and G1-2 fevers, which were manageable with acetaminophen and diphenhydramine, as well as G2 weight gain and G3 anemia. No dose-liming toxicity has been observed in any cohort. Three monotherapy patients (15 mcg/d) were evaluable for efficacy with ≥1 on-treatment scan; 2 had SD and 1 PD per RECIST 1.1 criteria. T cell activation, as shown by redistribution from the periphery (margination), was apparent in the first week of dosing for most patients. Compensatory myelopoiesis led to initial expansion of MDSC which were then depleted by AMV564. Increased cytotoxic T cell activation and T-helper (Th) 1 response was evidenced by increased T-bet positive CD4 and CD8 cells and controlled or decreased regulatory T cells. In some patients, effector memory CD8 cell populations (Tem and Temra) were expanded. Conclusions: AMV564 is safe and tolerable when administered SC at doses of 15 mcg/d alone and 5 mcg/d in combination with pembrolizumab. AMV564 depleted MDSC populations and altered T cell profiles consistent with activation of cytotoxic T cells and a Th1 response. Clinical trial information: NCT04128423 .

698 Targeting HLA-G-mediated immunosuppression with a first-in-class antagonist antibody

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A740-A740
Author(s):  
Douglas Hodges ◽  
Christina Kochel ◽  
Michael Totagrande ◽  
Jeffrey Jones ◽  
Megan Welch ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Nk Cells ◽  
Solid Tumors ◽  
Immune Cells ◽  
Target Cells ◽  
Human Antibody ◽  
Advanced Solid Tumors ◽  
Tumor Types

BackgroundHuman leukocyte antigen-G (HLA-G) is an immune checkpoint molecule that belongs to the non-classical HLA-class I family of receptors. HLA-G restrains immune cell activation and effector function by engaging with inhibitory receptors ILT2 and ILT4. While expression of HLA-G is highly restricted under normal healthy conditions, we have demonstrated that its expression in cancer is aberrantly upregulated and broadly detected across a variety of tumor types. Tizona Therapeutics has generated a novel, fully human antibody that specifically targets HLA-G and reverses HLA-G-mediated immunosuppression. Here we present in vitro and in vivo data demonstrating the functional impact of HLA-G blockade on immune cells and evidence to support the use of TTX-080 in the clinic to treat patients with advanced solid tumors.MethodsEvaluation of HLA-G expression in cancer was performed using immunohistochemistry, flow cytometry, and gene profiling. Expression of ILT2 and ILT4 was assessed on tumor infiltrating leukocytes by flow cytometry. To demonstrate the suppressive function of HLA-G, primary human NK cells, T cells, and monocyte-derived macrophages were cultured with target cells expressing HLA-G. TTX-080 was then evaluated for its ability to reverse this suppression. In addition, TTX-080 was investigated in vivo using a disseminated xenograft tumor model.ResultsExpression of HLA-G was detected on tumor cells and tumor infiltrating leukocytes across a variety of solid tumor types. TTX-080 blocked interaction of HLA-G with both ILT2 and ILT4 and restored cytotoxicity in multiple assays using either primary NK cells or NKL cell lines. Monocyte-derived macrophages expressing ILT2 and ILT4 exhibited decreased phagocytosis of HLA-G+ target cells; this inhibition was reversed with an antigen-binding fragment of TTX-080. TTX-080 was also able to reverse HLA-G-mediated suppression of ILT2+ CD8+ T cells as assessed by degranulation and proinflammatory cytokine secretion. Notably, mice with disseminated tumors had extended median survival when treated with a single dose of TTX-080.ConclusionsTTX-080 reverses HLA-G-mediated suppression of ILT2+ and ILT4+ immune cells that are found within the tumor microenvironment. Blockade of HLA-G using TTX-080 therefore has the potential to reverse broad immune suppression in patients with advanced solid tumors by reinvigorating CD8+ T cells, enhancing NK cytolytic activity, and increasing macrophage phagocytosis.

scholarly journals 788 A novel T- lymphocyte binding aptamer assembled into a bispecifc compound for the treatment of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A823-A823
Author(s):  
Irit Carmi Levy ◽  
Erez Lavi ◽  
Neta Zilony Hanin ◽  
Zohar Pode ◽  
Karin Mizrahi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Tumor Targeting ◽  
Specific Antigen ◽  
Therapeutic Agents ◽  
List Type ◽  
Bispecific T Cell Engager

BackgroundT-cell engagers are bispecific molecules directed against the CD3 complex on one end and a tumor specific antigen on the other end, allowing a physical link of T cell to a tumor cell, resulting in tumor killing and immune activation. Bispecific molecules harnessing and redirecting T-cells towards tumor cells are a promising therapeutic agents. Aptamers are single stranded oligonucleotides with binding and recognition propensities similar to those of antibodies. Aptamers have a number of advantages over bispecific antibodies including shorter generation time and low immunogenicity. Thus, aptamers capable of targeting T cells would have great potential for use as anti-cancer therapeuticsMethodsSystematic evolution of ligands by exponential enrichment (SELEX) methodology was employed in order to identify a novel CD3e binding aptamer. CD3 binding aptamer was subsequently linked into a bispecific T cell engager structure with a tumor-targeting aptameric arm. The tumor-targeting aptamer is developed by Aummune's proprietary tailored therapeutic platform.1 based on identifying functional aptamer sequences capable of specifically killing targeted tumor cells and sparing healthy tissue .Exemplary bispecific aptamers were tested for T cell stimulation by flow cytometry. In vivo antitumor activity was investigated in syngeneic and in xenograft tumor models.ResultsWe have successfully identified a novel CD3e –targeting aptamer with a Kd of 31nM. A bispecific T cell engager comprised of this aptamer and a tumor-targeting aptamer induced a potent stimulation of T cells in vitro, resulting in CD69 upregulation and IFNg secretion.Next, the CD3e targeting aptamer was hybridized to tumoricidal aptamers identified by Aummune's platform (VS12) to target either the human colon carcinoma HCT116 cells or (VS32) the murine triple negative breast cancer 4T1 cells. Both bispecific entities (CS6-VS12 and CS6-VS32) effectively lead to inhibition of tumor growth in vivo and increased survival in the corresponding models.ConclusionsOur data above provide a proof-of-concept for Aummune's Bispecific Aptamer efficacy and provide a framework for the clinical development of this novel tailored immune therapeutic agents. Indeed, we are currently in the process of developing a first-in-human clinical study in subjects with solid tumors.ReferenceMamet N, et al, Commun Biol 2020.

scholarly journals 850 Dual blockade of the EP2 and EP4 PGE2 receptors with TPST-1495 is an optimal approach for drugging the prostaglandin pathway

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A891-A891
Author(s):  
Brian Francica ◽  
Justine Lopez ◽  
Anja Holtz ◽  
Dave Freund ◽  
Dingzhi Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Whole Blood ◽  
List Type ◽  
Tumor Bearing ◽  
Dual Blockade ◽  
Cox 2 ◽  
Ct26 Tumor

BackgroundProstaglandin E2 (PGE2) is a bioactive lipid produced by tumor cells that drives disease progression through stimulating tumor proliferation, enhancing angiogenesis and suppressing immune function in the TME.1 PGE2 is also a mediator of adaptive resistance to immune checkpoint inhibitor therapy via the upregulation of cyclooxygenase-2 (COX-2). While the role of PGE2 signaling in cancer is clear, how best to inhibit PGE2 for cancer treatment remains under investigation. Inhibition of COX-1 and/or COX-2 has shown promising results in observational studies and meta-analyses, but inconsistent results in prospective studies. PGE2 signals through four receptors, EP1-4, that are variably expressed on tumor and immune cells and have distinct biological activities. The EP2/EP4 receptors signal through cAMP and drive pro-tumor activities, while EP1/EP3 receptors signal through calcium flux and IP3 and drive immune activation and inflammation. While COX-2 and single EP inhibitors continue to be developed, the nature of PGE2 signaling supports our rationale to inhibit PGE2 by dual antagonism of the pro-tumor EP2/EP4 receptors, while sparing the pro-immune EP1/EP3 receptors.MethodsWe utilized human and murine whole blood to perform in vitro characterization of PGE2/inhibitor activity. In vivo, CT26 tumors and APCmin/+ mice were used to model CRC and measure immune endpoints.ResultsIn mouse and human whole blood assays, dual blockade of EP2 and EP4 receptors with TPST-1495 reversed PGE2-mediated suppression of LPS induced TNF-α, while EP4 receptor antagonists were unable to block suppression at higher PGE2 concentrations. Similarly, in murine and human T cells in vitro, TPST-1495 inhibited PGE2-mediated suppression, resulting in a significant increase of IFN-γ production in response to stimulation with cognate peptide Ag. In vivo, TPST-1495 therapy alone also significantly reduced tumor outgrowth in CT26 tumor bearing mice, correlated with increased tumor infiltration by NK cells, CD8+ T cells, AH1-specific CD8+ T cells, and DCs. The induced NKp46+CD4-CD8- cell population appeared to have an important role in TPST-1495 efficacy, as significant anti-tumor activity was observed in murine models lacking T Cells, particularly CT26 tumor-bearing RAG2-/- mice. TPST-1495 monotherapy demonstrated a decrease of both the intestinal tumor size and number in Adenomatous Polyposis (APCmin/+) mice, as compared to a single EP4 antagonist.ConclusionsTPST-1495 is a potent inhibitor of PGE2 mediated immune suppression and is currently being evaluated in an ongoing Phase 1 first-in-human study (NCT04344795) to characterize PK, PD, safety, and to identify a recommended phase 2 dose for expansion cohorts in key indications and biomarker selected patients.ReferenceZelenay S, van der Veen AG, Böttcher JP, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 2015;162(6):1257–70. doi: 10.1016/j.cell.2015.08.015

scholarly journals 494 Phase 1 dose escalation and dose expansion study of an agonist redirected checkpoint (ARC) fusion protein, SL-279252 (PD1-Fc-OX40L), in subjects with advanced solid tumors or lymphomas

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A526-A526
Author(s):  
Melissa Johnson ◽  
Lilian Siu ◽  
David Hong ◽  
Patrick Schoffski ◽  
Vladimir Galvao ◽  
...  
Keyword(s):  
United States ◽  
T Cells ◽  
Fusion Protein ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Effector Memory ◽  
Advanced Solid Tumors ◽  
Anti Tumor Activity

BackgroundPD1-Fc-OX40L, is a hexameric, bi-functional fusion protein with an extracellular domain (ECD) of PD-1 (70 pM affinity to PD-L1) linked to the ECD of OX40L (324 pM affinity to OX40) through an Fc linker. The therapeutic activity of mPD1-Fc-OX40L in murine tumors was superior to PD1 blocking, OX40 agonist or combination antibody therapy.1MethodsThe first-in-human, Phase 1 dose escalation study is evaluating SL-279252 as monotherapy in patients (pts) with advanced solid tumors or lymphomas. Objectives include evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose (RP2D), pharmacokinetic (PK) parameters, pharmacodynamic (PD) effects, and anti-tumor activity per iRECIST.ResultsAs of 11 June 2021, 43 pts were enrolled and dosed intravenously with SL-279252 (median age 64 years; 56% male; median [range] of 3 [0–5] prior systemic therapies for metastatic disease): 30 pts were treated on schedule 1 (day 1, 8, 15, 29, then every 2 weeks ) from dose level 0.0001–6 mg/kg, and 13 pts treated on schedule 2 (weekly) from dose level 0.3–3 mg/kg. 58% of pts were PD-1/L1 inhibitor experienced, and most tumors lacked PD-L1 expression. Common (>15%) treatment emergent adverse events (AEs) of any grade (G) were constipation in 11 (26%) pts, back pain 8 (19%) pts, anemia 7 (16%) pts and decreased appetite 7 (16%) pts. Infusion-related reactions (G1/2) were noted in 3 (7%) pts. G3 treatment-related AEs (TRAEs) were neutropenia (2%) and hypercalcemia (2%); no G4/5 TRAEs or DLTs occurred. SL-279252 Cmax and AUC increased linearly up to 3mg/kg, and greater than proportional increase in AUC was observed at 6 mg/kg. The preliminary T½ was ~23 hours. Dose-dependent receptor occupancy on CD4+OX40+ T cells persisted for >7 days and these cells rapidly marginated from the peripheral blood post infusion. Increases in the number of proliferating central and/or effector memory T cells were seen in some pts at doses of ≥1mg/kg. Analysis of paired tumor biopsies is ongoing. Best response was 1 durable confirmed iPR (ocular melanoma, 4 prior systemic regimens) in a pt who remained on treatment for >1 yr, and iSD in 12 pts (1 unconfirmed iPR). iSD for > 24 wks occurred in 6/12 pts.ConclusionsSL-279252 is well-tolerated in pts with refractory solid tumors with no maximum tolerated dose (MTD) reached. OX40-dependent PD effects and durable anti-tumor activity was observed. Trends for PK/PD effects at ≥1 mg/kg suggests dose exploration in PD-L1 expressing cancers is warranted beyond 6 mg/kg.AcknowledgementsThanks are extended to study participants; Takeda Pharmaceutical Company, Boston, MA, United States; Cathrine Leonowens, PhD, Nuventra Pharma Sciences, Durham, NC, United States and Cadence Communications and Research, Thousand Oaks, CA, United States. This study is funded by Shattuck Labs, Inc. Austin, TX and Durham, NC, United States.Trial RegistrationNCT03894618ReferencesFromm G, de Silva S, Johannes K, Patel A, Hornblower JC, Schreiber TH. Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy. J Immunother Cancer 2018;6: 1–16.Ethics ApprovalThis study is being conducted in full conformity with the Declaration of Helsinki and was approved by all IRBs/ethics committees from each clinical site participating in the study. Specific approval numbers can be provided upon request.

scholarly journals 861 Reprogramming regulatory T cells (Treg) using a MALT1 inhibitor for cancer therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A902-A902
Author(s):  
Peter Keller ◽  
Irina Mazo ◽  
Yun Gao ◽  
Vijayapal Reddy ◽  
Francisco Caballero ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Phase 1 ◽  
Treg Cells ◽  
Cell Killing ◽  
Therapeutic Window ◽  
List Type ◽  
Link Type

BackgroundMALT1 protease is a promising target in aggressive lymphomas1, and two phase 1 clinical trials in hematological cancers are ongoing (NCT03900598, NCT04876092). More recently, MALT1 protease inhibition was also shown to reprogram regulatory T cells (Treg) in solid tumors, causing them to lose their immunosuppressive function and secrete interferon-gamma (IFN).2 Changes in Treg metabolism in the tumor microenvironment (TME) may account for their destabilization and selective susceptibility to reprogramming in tumor tissue.3 4 5 While strong MALT1 inhibition can cause Treg depletion in blood and induce autoimmune toxicity,6 a therapeutic window for a differentiated MALT1 inhibitor that reprograms destabilized Treg in the TME before affecting Treg in healthy tissue may exist.2 MPT-0118 is an orally dosed MALT1 inhibitor developed to reprogram destabilized Treg in the TME without causing autoimmune symptoms. A Phase 1/1b dose-escalation and cohort-expansion clinical trial evaluating MPT-0118 is underway (NCT04859777).MethodsHuman xenograft models of lymphoma were used to assess the direct activity of MPT-0118 on MALT1-dependent (but not not MALT1-independent) hematologic tumors. Effects of MPT-0118 on solid tumors were determined in syngeneic cancer models. Human and mouse tumor tissues were evaluated for Treg reprogramming by in situ hybridization or flow cytometry. Patient-derived organotypic tumor spheroids were assessed for immune-mediated cell killing. Studies in rodents and dogs assessed pharmacokinetics (PK) and safety.ResultsMPT-0118 was selective and effective in preventing growth of aggressive MALT1 protease-dependent lymphomas. Beyond direct activity on hematologic malignancies, MPT-0118 also increased anti-tumor immune responses as single-agent or in combination with anti-PD-1 in syngeneic tumor models that are otherwise unresponsive to immune checkpoint blockade (ICB). MPT-0118-treated syngeneic tumors showed an increase in IFN-secreting Treg, associated with decelerated tumor growth. PK studies reveal that MPT-0118 has a high volume of distribution, and effective inhibitor concentrations are reached in the murine tumors upon oral dosing. The drug candidate caused tumor-associated Treg to produce IFN without changing the frequency of Treg circulating in the blood. Ex vivo, MPT-0118 induced Treg reprogramming in tumors resected from patients with colorectal and endometrial cancers and cell killing in spheroids derived from patients with colorectal cancer.ConclusionsThe MALT1 inhibitor MPT-0118 is a clinical candidate for treating MALT1-expressing lymphomas and Treg-infiltrated solid tumors. MPT-0118 exploits the therapeutic opportunity presented by destabilized Treg in the TME. Treg reprogramming represents a novel strategy with the potential to improve responses to ICB therapy in a broad range of solid tumors.ReferencesNagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, Hlahla D, Neuenschwander M, Peter von Kries J, Hadian K, Dörken B, Lenz P, Lenz G, Schendel DJ, Krappmann D. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell 2012 December 11;22(6):825–37.Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN, Seruggia D, Usmani SM, Misale S, Zappulli V, Carrizosa E, Mani V, Ligorio M, Warner RD, Medoff BD, Marangoni F, Villani AC, Mempel TR. Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy. Nature 2019 June;570(7759):112–116.Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, Dhungana Y, Chapman NM, Long L, Saravia J, Vogel P, Chi H. Lipid signalling enforces functional specialization of Treg cells in tumours. Nature 2021 March;591(7849):306–311.Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, Watson MJ, Leftin A, Maniyar R, Verma S, Lubin M, Ko M, Mane MM, Zhong H, Liu C, Ghosh A, Abu-Akeel M, Ackerstaff E, Koutcher JA, Ho PC, Delgoffe GM, Blasberg R, Wolchok JD, Merghoub T. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 2021 March;591(7851):652–658.Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, Shuai Y, Normolle DP, Kirkwood JM, Ferris RL, Delgoffe GM, Bruno TC, Workman CJ, Vignali DAA. Interferon-γ drives Treg fragility to promote anti-tumor immunity. Cell 2017 June 1;169(6):1130–1141.e11.Martin K, Junker U, Tritto E, Sutter E, Rubic-Schneider T, Morgan H, Niwa S, Li J, Schlapbach A, Walker D, Bigaud M, Beerli C, Littlewood-Evans A, Rudolph B, Laisney M, Ledieu D, Beltz K, Quancard J, Bornancin F, Zamurovic Ribrioux N, Calzascia T. Pharmacological inhibition of MALT1 protease leads to a progressive IPEX-Like pathology. Front Immunol 2020 April 30;11:745.

scholarly journals 535 A phase I/II study of REGN7075 (EGFRxCD28 costimulatory bispecific antibody) in combination with cemiplimab (anti–PD-1) in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A565-A565
Author(s):  
Nehal Lakhani ◽  
Melissa Johnson ◽  
Roman Groisberg ◽  
Hyunsil Han ◽  
Kerry Casey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Group Performance ◽  
Bispecific Antibodies ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundT-cell redirecting bispecific antibodies (bsAbs) are therapeutics that recognize two distinct antigens: a tumor-associated antigen on tumor cells to promote recruitment of T-cells to the tumor, and a receptor on T-cells to potentiate anti-tumor activity. REGN7075 is a human immunoglobulin G4-based costimulatory bsAb designed to bridge epidermal growth factor receptor (EGFR) positive tumor cells with CD28 positive T-cells and to provide amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor, through the activation of CD28 co-stimulation. In genetically humanized immunocompetent mouse models, REGN7075 in combination with anti–PD-1 (antibody directed against programmed cell death-1 receptor) improved anti-tumor activity compared with either single agent alone.1MethodsThis is an open label, Phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab in patients with advanced solid tumors (NCT04626635). Patients must have a protocol-defined advanced solid tumor, be ≥18 years of age (≥20 years in Japan), have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naïve to anti–PD-1/anti–PD-ligand(L)1.This study includes dose escalation (a 4+3 design modified from 3+3; Part 1) and expansion phases (Part 2). In Part 1, patients will receive a lead-in of REGN7075 monotherapy for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or other stopping criterion is met. Once a recommended Phase 2 dose is determined in Part 1, four tumor-specific expansion cohorts will be opened: non-small cell lung cancer (PD-L1 ≥50%), triple-negative breast cancer, colorectal cancer (microsatellite stable), and cutaneous squamous cell carcinoma. Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. This study is currently open to enrollment.Trial RegistrationClinicalTrials.gov identifier NCT04626635.ReferencesWaite JC, Wang B, Haber L, et al. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med 2020;12:2325.Ethics ApprovalThis study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board/ethics committee at each participating study site.ConsentAll patients provided written informed consent.

Allogeneic Suicide Gene-Modified T Cells (aSGMTC) Are Highly Cytotoxic to Non-Hematopoietic Tumor Cell Lines: Rationale for the Production of a Bank of aSGMTC for the Treatment of Solid Tumors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2459-2459
Author(s):  
Laurent Mailly ◽  
Celine Leboeuf ◽  
Christophe Ferrand ◽  
Pierre Tiberghien ◽  
Gaetan Bour ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Cytotoxic Activity ◽  
Solid Tumors ◽  
Hela Cells ◽  
Suicide Gene ◽  
Effector Memory ◽  
Proliferative Potential ◽  
Huh7 Cells

Abstract Abstract 2459 Poster Board II-436 Suicide gene therapy using alloreactive T cells is an efficient immunotherapeutic strategy for hematologic malignancies (Tiberghien et al, Blood 2001). We hypothesized that solid tumors, such as hepatocellular carcinoma (HCC) could be targeted by intratumoral infusion of allogeneic T cells produced from normal donors: the tumor cells would be recognized, not as being tumoral, but as being allogeneic. The prior introduction into such T cells of a suicide gene encoding the herpes simplex virus thymidine kinase (HSV-tk) that confers sensitivity to a pro-drug, ganciclovir, would allow controlling their potentially deleterious alloreactivity toward normal patient's tissues, as we demonstrated in bone marrow-transplanted patients with >10 years follow-up (Deschamps et al, Blood 2007). Our aim is to demonstrate the feasibility of this approach and to create a bank of “ready-to-use” allogeneic gene-modified T cells (GMC) for potential future in vivo evaluation and clinical use. Normal donors' peripheral blood mononuclear cells (PBMC) activated by CD3 monoclonal antibodies and Interleukin (IL)-2 were retrovirally transduced at d3 with a vector encoding a CD34/HSV-tk fusion protein. CD34+ sorted GMC were expanded with IL-2 until d14 and assessed for cytotoxicity against HeLa cells (human epithelial adenocarcinoma) and Huh7 cells (human hepatoma) by coincubation for 1-6 days at different effector:target (E:T) ratios, then staining of residual viable adherent targets by crystal violet. Allogeneic GMC (>90% T cells with a reversed CD4:CD8 ratio (0.58+/-0.06, n=9) and a predominant CD45RA- CD27- effector/memory phenotype) exhibited a strong and ganciclovir-sensitive cytotoxicity against Huh7 cells : >80% cell lysis of Huh7 cells were usually observed at an E:T ratio = 4:1 after 24h of co-incubation. Ex vivo-expanded, but non transduced, control cells were similarly cytotoxic, indicating that the retroviral transduction did not affect the cytotoxic activity of GMC. By contrast, PBMC were weakly cytotoxic, since no lysis of Huh7 cells was detectable after 24h co-incubation and <30% lysis were observed at d6 at an E:T ratio = 40:1. Similar results were observed with HeLa cells, that were even more sensitive to GMC-mediated lysis than Huh7. Acquisition of a cytotoxic activity was dependent upon the cell culture conditions: replacing the CD3 activation by CD3/CD28 or IL-2 by IL-7 was associated with increased proliferative potential and frequencies of cells with a so-called “naïve” (CD45RA+ CD27+) and central memory (CD45RA- CD27+) phenotype, but with a decreased cytotoxic activity. In vivo studies demonstrated that GMC induce tumor cell regression when coinfused with luciderase-expressing HeLa cells. Our results suggest that alloreactive GMC may represent a novel strategy for treatment of solid tumors which deserves further evaluation in vivo. Disclosures: No relevant conflicts of interest to declare.

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