Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1399-1403 ◽  
Author(s):  
Gullu Gorgun ◽  
Francine Foss
Keyword(s):  
T Cell ◽  
B Cell ◽  
Retinoic Acid Receptor ◽  
Interleukin 2 ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Immunomodulatory Effects ◽  
Denileukin Diftitox ◽  
High Affinity ◽  
T Cell Lymphomas

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10−6 to 10−10 M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R–targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.

Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous T-cell lymphoma.

1993 ◽  
Vol 11 (9) ◽  
pp. 1682-1690 ◽  
Author(s):  
P Hesketh ◽  
P Caguioa ◽  
H Koh ◽  
H Dewey ◽  
A Facada ◽  
...  
Keyword(s):  
T Cell ◽  
Fusion Protein ◽  
Interleukin 2 ◽  
Common Adverse Effect ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
T Cell Lymphomas ◽  
Hepatic Transaminases ◽  
Heavily Pretreated ◽  
Pretreated Patients

PURPOSE A phase I trial in patients with refractory hematologic malignancies was performed at our institution to test the clinical relevance of the selective cytotoxic activity of the interleukin-2 (IL-2)-diphtheria toxin fusion protein, DAB486IL-2. A subset of five patients from this trial, all with cutaneous T-cell lymphomas (CTCL), forms the basis of this report. PATIENTS AND METHODS Two treatment schedules were used. One patient received DAB486IL-2 at a dose of 0.075 mg/kg/d intravenous (i.v.) bolus over 15 minutes daily for 5 consecutive days. The other four patients received DAB486IL-2 at a dose of 0.1 mg/kg as an i.v. infusion over 180 minutes weekly for 5 consecutive weeks. RESULTS Three of the five CTCL patients achieved significant tumor responses. One patient attained a complete clinical and pathologic response (CR), which has been sustained without any interval treatment for 33+ months. Two other patients achieved partial responses (PRs) of 17+ and 4 months' duration, respectively. Treatment was well tolerated. The most common adverse effect was a transient increase in hepatic transaminases experienced by all five patients. CONCLUSION The growth factor-cytotoxin fusion protein DAB486IL-2 demonstrated significant clinical activity with acceptable toxicity in a group of heavily pretreated patients with CTCL.

Denileukin Diftitox (ONTAK) Plus CHOP Chemotherapy in Patients with Peripheral T-Cell Lymphomas (PTCL), the CONCEPT Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3449-3449 ◽  
Author(s):  
Francine Foss ◽  
Nelida Sjak-Shie ◽  
Andre Goy ◽  
Eric Jacobsen ◽  
Ranjana Advani ◽  
...  
Keyword(s):  
T Cell ◽  
Recombinant Dna ◽  
Nk Cell ◽  
Tumor Lysis Syndrome ◽  
Interleukin 2 ◽  
Clinical Activity ◽  
Chop Chemotherapy ◽  
First Line ◽  
Denileukin Diftitox ◽  
Grade 3

Abstract PTCL are an aggressive group of lymphomas comprising a number of histopathologic subtypes for which CHOP chemotherapy has been the standard first-line regimen at many centers. Denileukin diftitox (Dd) is a recombinant DNA-derived cytotoxic protein composed of diphtheria toxin fragments A and B and the full length sequence of human interleukin-2 (IL-2). Dd targets T-cells expressing the intermediate and high-affinity IL-2 receptor. Because the mechanism of action of Dd is distinct from traditional cytotoxic chemotherapy and Dd has exhibited minimal myelosuppression, we evaluated the safety, tolerability, and efficacy of combining Dd with CHOP as first-line therapy for patients with PTCL according to the REAL classification. (Pts with mycosis fungoides or Sezary syndrome were not included.) Dd was administered at 18 mcg/kg/day on Days 1 and 2 followed by CHOP on Day 3, and G-CSF support starting Day 4, every 3 weeks for up to 6 cycles. Evaluation of response is performed after every 2 cycles of treatment. Results: Forty-one pts, 18 male/23 female, have been enrolled to date, with a median age of 52. Ten pts are not evaluable for response: 5 discontinued due to an adverse event (AE) prior to assessment of response; 3 due to lack of measurable disease at baseline; and 2 are too early to evaluate. For the 31 response-evaluable patients, the overall response rate is 90%, with 71% (22/31) CR or CRu, 19% (6/31) PR, 6% (2/31) SD, and 3% (1/31) PD. Ten of 28 responders (36%) have progressed, with a median duration of response of 13 months. PTCL subtype No. of Patients No. evaluable Responses ORR PTCL-nos 20 15 3 CR, 5 CRu, 4 PR, 2 SD, 1 PD 80% Angioimmunoblastic 10 9 3 CR, 5 CRu, 1 PR 100% Anaplastic large cell 6 4 2 CR, 2 CRu 100% Enteric T-cell 2 1 1 CRu 100% Hepatosplenic 1 0 n/a n/a Nasal/nasal type T/NK cell 1 1 1 CRu 100% Subcutaneous panniculitic T-cell 1 1 1 PR 100% Toxicities have generally been grade 1–2, were transient, and caused few dose modifications. The most common have been fatigue (62%), nausea (44%), anemia (38%), sensory neuropathy (33%), hypoalbuminemia (33%), elevated ALT (30%), dyspnea (28%), thrombocytopenia (30%), leukopenia (28%), fever (25%), elevated AST (25%), lymphopenia (25%), and hyperglycemia (25%). Forty-three percent (17/40) of patients experienced one or more grade 3–4 hematological toxicities and 40% (16/40) of patients experienced one or more grade 3–4 non-hematological toxicities. Five patients discontinued the study due to AEs, all occurring prior to Cycle 2, for: infusion-related anaphylaxis; elevated LFTs; port-related staph sepsis; pneumonia; and a death possibly resulting from tumor lysis syndrome and rhabdomyolysis. Conclusion: The combination of Dd plus CHOP has a generally manageable safety profile and to date has exhibited promising clinical activity in PTCL.

Phase I Trial of Fenretinide (4-HPR) Intravenous Emulsion for Hematologic Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2581-2581 ◽  
Author(s):  
Ann Mohrbacher ◽  
Martin Gutierrez ◽  
Anthony J. Murgo ◽  
Shivaani Kummar ◽  
C. Patrick Reynolds ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
High Performance ◽  
Dose Range ◽  
Systemic Exposure ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
T Cell Lymphomas ◽  
Oral Capsule

Abstract Background: 4-HPR is a cytotoxic retinoid with broad anti-cancer activity in preclinical studies, but oral capsule 4-HPR had limited bioavailability and activity in clinical trials. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase 4-HPR systemic exposure. Methods: ILE 4-HPR was administered as a continuous intravenous infusion for 5 of every 21 days and systemic toxicities, clinical response, and pharmacokinetics (PK) assessed. Simon design dose escalation proceeded with a 100% increase per dose level until moderate toxicity in 2 patients or 1 dose-limiting toxicity (DLT). Ten dose levels were planned starting at 80 mg/m2/day, increasing until 1810 mg/m2. Plasma 4-HPR levels were measured by high performance liquid chromatography. Results: To date, 17 patients have been enrolled. At dose level 10 (1810 mg/m2/day), 2 patients experienced a DLT of grade 4 hypertriglyceridemia, 1 patient with transient grade 2 pancreatitis. A de-escalation to dose level 9 (1280 mg/m2/day) enrolled 5 patients: 1 had asymptomatic Grade 4 hypertriglyceridemia, 1 patient experienced pleural effusions that resolved after pleurocentesis. A de-escalation to dose level 8 (905 mg/m2/day) enrolled 5 pts: two patients experienced asymptomatic Grade 4 hypertriglyceridemias that resolved after stopping the infusion; enrollment is ongoing. PK showed a linear relationship of dose to plasma level, with steady-state 4-HPR levels of 25 μM (640 mg/m2, level 7); 54 μM (1280 mg/m2, level 9) and 62 μM (1810 mg/m2, level 10). Responses to date include a transient response in a non-Hodgkins lymphoma at 320 mg/m2, in two angioimmunoblastic T-cell lymphomas, an 8-month partial response at 1810 mg/m2/day and a 4+ month unconfirmed complete response at 905 mg/m2/day, and in a histone deacetylase inhibitor-refractory cutaneous T cell lymphoma, a 10+ month molecular complete response at 1280 mg/m2. All patients were heavily pretreated. The DLT of hypertriglyceridemia is likely related to the intralipid formulation vehicle accounting for 5/6 DLTs observed, all reversible. Conclusions: ILE 4-HPR can be safely administered and obtained 4-HPR plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR. Durable clinical activity was observed in T cell lymphomas in the dose range 905–1810 mg/m2. Supported in part by NCI U01CA62505 and the NCI RAID program.

scholarly journals Denileukin Diftitox (Ontak) as Maintenance Therapy for Peripheral T-Cell Lymphomas: Three Cases with Sustained Remission

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Alejandra C. Fuentes ◽  
Ellen Szwed ◽  
Cathy D. Spears ◽  
Sandeep Thaper ◽  
Long H. Dang ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Complete Remission ◽  
Maintenance Therapy ◽  
Single Agent ◽  
Interleukin 2 ◽  
Sustained Remission ◽  
Denileukin Diftitox ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

Peripheral T-cell lymphomas (PTCL) are rare but markedly aggressive forms of non-Hodgkin’s lymphoma (NHL). They carry a poor prognosis, with current therapeutic approach being generally ineffective. The most employed first-line treatment is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which still results in high rates of relapses. Denileukin diftitox is a fusion protein combining the cytotoxic portion of the diphtheria toxin and the receptor-binding domain of the interleukin-2 (IL-2) molecule, thereby targeting cells expressing the IL-2 receptor, including both T-cell and B-cell lymphomas. It has been approved for the treatment of cutaneous T-cell lymphomas, and it has documented activity in PTCL both as a single agent and as part of combination therapy. This report documents three cases of PTCL where denileukin diftitox has been used as long-term maintenance therapy after complete remission was achieved. While the overall survival rate of patients with advanced stage, refractory PTCL is generally poor (with median overall survival of 5.5 months), the three patients described in this report are all experiencing an ongoing complete remission for more than four years.

scholarly journals Expression of interleukin 2 receptors on activated human B cells.

1984 ◽  
Vol 160 (5) ◽  
pp. 1450-1466 ◽  
Author(s):  
T A Waldmann ◽  
C K Goldman ◽  
R J Robb ◽  
J M Depper ◽  
W J Leonard ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Interleukin 2 ◽  
Antigen Expression ◽  
Pokeweed Mitogen ◽  
Binding Studies ◽  
High Affinity ◽  
Activated B Cells

Using anti-Tac, a monoclonal anti-interleukin 2 (IL-2) receptor antibody, we have explored the possibility that certain activated B cells display receptors for IL-2. Resting normal B cells and unselected B cell lines established from normal individuals were Tac antigen negative. In contrast, the cell surface Tac antigen expression was demonstrable on 6 of 10 B cell lines from patients with Burkitt's lymphoma, 5 of 6 B cell lines derived from patients with HTLV-I-associated adult T cell leukemia (including all four that had integrated HTLV-I into their genome), and on certain normal B cells activated with pokeweed mitogen. Furthermore, cloned Epstein-Barr virus-transformed B cell lines derived from Tac-positive normal B cells continued to express the Tac antigen in long-term cultures and manifested high affinity IL-2 receptors identified in binding studies with purified radiolabeled IL-2. The line 5B4 developed in the present study could be induced with purified JURKAT-derived or recombinant IL-2 to express a larger number of IL-2 receptors. Furthermore, the addition of IL-2 to the 5B4 B cell line augmented IgM synthesis, which could be blocked by the addition of anti-Tac. The size of the IL-2 receptors expressed on the cloned normal B cell lines was similar (53,000-57,000 daltons) to that of receptors on phytohemagglutinin-stimulated T cell lymphoblasts. Thus, certain malignant and activated normal B cells display the Tac antigen and manifest high affinity receptors for IL-2. These data suggest that IL-2 may play a role in the differentiation of activated B cells into immunoglobulin-synthesizing and -secreting cells.

scholarly journals Point Mutation Specific Antibodies in B-Cell and T-Cell Lymphomas and Leukemias: Targeting IDH2, KRAS, BRAF and Other Biomarkers RHOA, IRF8, MYD88, ID3, NRAS, SF3B1 and EZH2

Diagnostics ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 600
Author(s):  
Kunwar Singh ◽  
Sumanth Gollapudi ◽  
Sasha Mittal ◽  
Corinn Small ◽  
Jyoti Kumar ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Point Mutation ◽  
Point Mutations ◽  
Hematologic Malignancies ◽  
Structural Features ◽  
Genetic Mutations ◽  
Genetic Sequencing ◽  
Specific Antibodies ◽  
T Cell Lymphomas

B-cell and T-cell lymphomas and leukemias often have distinct genetic mutations that are diagnostically defining or prognostically significant. A subset of these mutations consists of specific point mutations, which can be evaluated using genetic sequencing approaches or point mutation specific antibodies. Here, we describe genes harboring point mutations relevant to B-cell and T-cell malignancies and discuss the current availability of these targeted point mutation specific antibodies. We also evaluate the possibility of generating novel antibodies against known point mutations by computationally assessing for chemical and structural features as well as epitope antigenicity of these targets. Our results not only summarize several genetic mutations and identify existing point mutation specific antibodies relevant to hematologic malignancies, but also reveal potential underdeveloped targets which merit further study.

scholarly journals A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 183-183 ◽  
Author(s):  
Stephen Ansell ◽  
Martin E Gutierrez ◽  
Margaret A. Shipp ◽  
Douglas Gladstone ◽  
Alison Moskowitz ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Food And Beverage

Abstract Introduction: Nivolumab (nivo) is a fully human IgG4 monoclonal antibody (mAb) targeting programmed death receptor-1 (PD-1). Nivo has demonstrated clinical activity and an acceptable safety profile in a phase 1b study (NCT01592370; CheckMate 039) in patients (pts) with relapsed/refractory hematologic malignancies. In pts diagnosed with Hodgkin lymphoma (HL), after a median 86 weeks of follow-up, 7/20 responders maintained a response for >1.5 years (Ansell S et al. Blood 2015;126:583), and after a median follow-up of 67 weeks, clinical activity (investigator-assessed objective response rate) was demonstrated in follicular lymphoma (FL; 40%), diffuse large B-cell lymphoma (DLBCL; 36%), mycosis fungoides (15%), and peripheral T-cell lymphoma (PTCL; 40%) (Lesokhin AM et al. J Clin Oncol 2016;34:2698). CheckMate 039 also included a cohort of pts who had received nivo in combination with ipilimumab (ipi), a fully human mAb targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4). Combination of CTLA-4 and PD-1 blockade has shown superior efficacy compared with nivo or ipi alone in preclinical studies and solid tumor malignancies (Wolchok JD et al. N Engl J Med 2013;369:122; Larkin JM et al. N Engl J Med 2015;373:22; Antonia SJ et al. Lancet Oncol 2016;17:883). The aim of this cohort study was to evaluate the safety and efficacy of combined immune checkpoint blockade (nivo+ipi) in pts with the following hematologic malignancies: HL, B-cell non-Hodgkin lymphoma (B-NHL; FL and DLBCL), T-cell NHL (T-NHL; cutaneous T-cell lymphoma [CTCL] and PTCL]), and multiple myeloma (MM). Methods: Nivo+ipi were given at 3 mg/kg IV and 1 mg/kg IV, respectively, every 3 weeks for 4 doses, followed by nivo monotherapy (3 mg/kg) every 2 weeks for up to 2 years. Pts with any of the above histologies, relapsed or refractory disease after ≥2 prior lines of therapy, and adequate organ function were included in the study. Prior systemic therapy may have included chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Prior anti-PD-1 therapy and allogeneic (allo)-HSCT were not permitted. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival (PFS). Results: In total, 65 pts were treated with nivo+ipi (31 HL, 15 B-NHL, 11 T-NHL, 7 MM, and 1 with primary mediastinal B-cell lymphoma [PMBL] who was included in the overall safety cohort only). Median (range) number of prior systemic therapies was 4 (2, 10; HL), 3, (1, 16; B-NHL), 4 (1, 11; T-NHL), and 5 (2, 20; MM). Among patients with HL, only 13% (4/31) had prior auto-HSCT. 2 pts with HL and 1 with T-NHL proceeded to allo-HSCT after stopping study therapy. Across all cohorts, median follow-up was 11.4 months. 5 pts (8%) discontinued due to a drug-related adverse event (AE). The most common drug-related AEs of any grade were fatigue (17 pts [26%]), pyrexia (15 [23%]), and diarrhea (12 [18%]). 19 pts (29%) had a drug-related AE of grade ≥3. 31 pts (48%) had a serious AE. 24 pts (37%) died: HL 2 pts, B-NHL 11, T-NHL 6, MM 4, PMBL 1. Among those pts, 22 (34%) were from disease progression (HL 2 pts, B-NHL 10, T-NHL 5, MM 4, PMBL 1); no deaths were due to an AE. Clinical outcome data are presented (Table). Conclusions: These are the first reported data of combination checkpoint blockade therapy in hematologic malignancies. Overall, the combination of nivo+ipi in these heavily pretreated patients demonstrated a safety and efficacy profile similar to that previously reported for nivo monotherapy in HL, NHL, and MM. Additional follow-up may further clarify the role of ipi in this cohort of patients. In this predominantly transplant-naïve group of patients with HL, the efficacy of nivo+ipi was similar to that seen in patients with relapsed/refractory HL treated with nivo alone. Funding: Bristol-Myers Squibb (BMS). Medical writing: S Addison, Caudex, funded by BMS Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Gutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging; Incyte Corporation: Consultancy; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage. Shipp:Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Moskowitz:Seattle Genetics: Research Funding; Seattle Genetics, Merck: Consultancy. Borello:Bristol-Myers Squibb: Research Funding, Speakers Bureau. Popa-Mckiver:Bristol-Myers Squibb: Employment, Equity Ownership. Farsaci:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Armand:Sequenta Inc: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Roche: Research Funding; Merck: Consultancy, Research Funding.

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

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