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

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.

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0347 ◽

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.

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0412 ◽

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.

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401 Phase 1/2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 with or without immune checkpoint inhibitor in patients with advanced HER2-expressing solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0401 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A426-A426

Author(s):

Manish Sharma ◽

Ecaterina Ileana Dumbrava ◽

Richard Carvajal ◽

Daniel Catenacci ◽

Leisha Emens ◽

...

Keyword(s):

Adverse Events ◽

Solid Tumors ◽

Dose Escalation ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Phase 1 ◽

List Type ◽

Dependent Manner ◽

Antibody Conjugates

BackgroundIn spite of advances made in the management of patients with HER2-expressing or -driven solid tumors, there remains a significant unmet need for novel approaches to improve patient outcomes. Intratumoral delivery of antitumor antibodies and immunostimulatory adjuvants such as toll-like receptor (TLR)7/8 agonists has been shown to activate tumor resident antigen-presenting cells (APCs), driving uptake, processing, and presentation of tumor neoantigens to T cells that mediate antitumor immunity. BDC-1001 is delivered systemically and has demonstrated superior preclinical biology. This novel ISAC consists of an investigational biosimilar of the humanized monoclonal antibody trastuzumab chemically conjugated to a TLR7/8 agonist with a non-cleavable linker. BDC-1001 activates human myeloid APCs in addition to retaining antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Studies in trastuzumab-resistant xenograft models and syngeneic tumor models indicate that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, leading to complete tumor regression in a TLR- and Fc receptor-dependent manner.1 2 Importantly, BDC-1001 did not induce interstitial lung disease, cytokine release syndrome, or thrombocytopenia in non-human primate studies. A four-part phase 1/2, first-in-human study has been initiated that evaluates BDC-1001 with or without (±) an immune checkpoint inhibitor targeting PD-1 in patients with HER2-expressing or HER2-amplified advanced/metastatic solid tumors.MethodsThis dose-escalation and dose-expansion study is enrolling up to 390 patients with HER2-expressing (IHC2+ or 3+ protein, irrespective of gene amplification) or HER2-amplified (by in situ hybridization or next-generation sequencing) advanced solid tumors. Primary objectives of the dose-escalation phase are to define safety and tolerability and determine the recommended phase 2 dose of BDC-1001 as monotherapy (Part 1) and in combination with an immune checkpoint inhibitor (Part 2). Part 2 is planned to start once BDC-1001 safety data are available. Primary endpoints include incidence of 1) adverse events and serious adverse events; 2) dose-limiting toxicities within a 3+3 design; and 3) potential immune-related toxicities. The dose-expansion portion of the trial will evaluate preliminary antitumor activity of BDC-1001 alone (Part 3) and in combination with an immune checkpoint inhibitor (Part 4). Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. These exploratory studies will help elucidate the mechanism of action and seek to identify biomarkers associated with BDC-1001 biological activity with or without immune checkpoint inhibitor. This global study is currently recruiting patients.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov (NCT04278144).Ethics ApprovalThe study and the protocol were or will be approved by the Institutional Review Board or ethics committee at each site.ConsentN/AReferencesAckerman, et al. TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation leading to enhanced effector function and anti-tumor immunity in pre-clinical models. Cancer Res. 2019:79 [13 Suppl]:Abstract 1559.Ackerman, et al. HER2-targeting TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation and anti-tumor immune responses in a TLR- and FcR- dependent manner. J Immunother Cancer 2019;7:283

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Specialized regulatory T cells control venous blood clot resolution through SPARC

Blood ◽

10.1182/blood.2020005407 ◽

2020 ◽

Author(s):

Fatemeh Shahneh ◽

Grill Alexandra ◽

Matthias Klein ◽

Felix Frauhammer ◽

Tobias Bopp ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Matrix Metalloproteinase ◽

Blood Clot ◽

Venous Blood ◽

Treg Cells ◽

Therapeutic Window ◽

Cysteine Rich Protein ◽

Treg Population ◽

Blood Clots

The cells and mechanisms involved in blood clot resorption are only partially known. We show that regulatory T (Treg) cells accumulate in venous blood clots and regulate thrombolysis by controlling the recruitment, differentiation and matrix metalloproteinase (MMP) activity of monocytes. We describe a clot Treg population that forms the matricellular acid- and cysteine-rich protein (SPARC), show that SPARC enhances monocyte MMP activity and that SPARC+ Treg are crucial for blood clot resorption. By comparing different treatment times, we define a therapeutic window of Treg expansion that accelerates clot resorption.

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501 Survival and immune response data from intratumoral INT230–6 alone (IT-01) and with pembrolizumab [KEYNOTE-A10] in subjects with locally advanced, unresectable and metastatic solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.501 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A533-A533

Author(s):

Jacob Thomas ◽

Anthony El-Khoueiry ◽

Anthony Olszanski ◽

Nilofer Azad ◽

Giles Whalen ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Prognostic Factors ◽

Solid Tumors ◽

Cd8 T Cells ◽

Phase 1 ◽

Prognostic Score ◽

Locally Advanced ◽

Cancer Center ◽

List Type

BackgroundBackground: Study IT-01 (KEYNOTE-A10) evaluates INT230-6, a novel formulation of cisplatin (CIS) and vinblastine (VIN) with an amphiphilic cell penetration enhancer designed for intratumoral (IT) administration, as monotherapy and in combination with pembrolizumab (PEM). In preclinical studies, INT230-6 increases drug dispersion throughout the tumor, allows drug diffusion into cancer cells and recruits dendritic, CD4 and CD8 T cells. The addition of PEM improves these responses in mouse models.MethodsIT-01 is an open-label phase 1/2 study, currently enrolling adult subjects with solid tumors in phase 2. The study assesses the safety and efficacy of INT230-6 IT Q2W up to 5 doses as monotherapy or with PEM 200mg Q3W. Biopsies from injected tumor are taken pretreatment and Day 28 for immunohistochemistry (IHC) analysis.ResultsFifty-seven INT230-6, two INT230-6 then PEM combination, and thirteen INT230-6 + PEM combination subjects were enrolled having a median of 4 prior therapies (0, 10). Median age was 62. 20+ cancer types were accrued; breast cancer and sarcoma were the most frequent. Over 500 image guided INT230-6 IT injections were given (253 to deep tumors) at doses of 0.3 to 172mL (86 mg CIS, 17.2 mg VIN) in a single session (contains higher amounts than typical IV chemo doses). PK shows that 95% of INT230-6 active agents remain in the tumor.1 The most common (>25%) related adverse events (AEs) for INT230-6 alone were localized pain (59%), nausea (37%), and fatigue (29%). Safety profile of the PEM combination was similar. There were no related grade 4 or 5 AEs in either arm. The median overall survival (mOS) estimated with removal of <2cm3 and >700cm3 tumor burdens was 433 days for monotherapy (n=51) and 513 days for PEM combination (n=12), which compares favorably to results seen in basket studies of patients having similar prognostic factors (ECOG, LDH, # of metastatic sites).2 IHC results indicate influx of CD4 and CD8 T-cells in injected lesions. No meaningful changes were observed in circulating inflammatory cytokines. Abscopal effects in the monotherapy arm were observed in 15 visceral/deep lesions in 11 patients, primarily who received an INT230-6 dose >50% of their total tumor burden (TTB).ConclusionsINT230-6 is well tolerated when administered IT as monotherapy and combined with PEM. Data suggests that INT230-6 prolongs survival compared to published basket studies in patients with similar prognostic factors. IHC and abscopal results indicate dosing INT230-6 may also activate a T-cell mediated immune response.AcknowledgementsN/ATrial RegistrationNCT# 03058289ReferencesOwelien. Historical PK data from IV administration. J Cancer Res 1977; 8.Abstract. Wagner M, et al. Validation of the Royal Marsden Hospital (RMH) prognostic score in 100 patients with advanced sarcoma enrolled in early phase clinical trials at a major cancer center. JCO 2015. https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.10558Ethics ApprovalThe protocol was approved by an institutional review board, independent ethics committee, or research ethics board at each institution. All subjects or their legally acceptable representative provided written informed consent before screening. The study was designed, undertaken, and reported in accordance with the Declaration of Helsinki, and is registered with clinicaltrial.gov with registration no NCT03058289.

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.012 ◽

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.

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P856 AVID200, first-in-class TGF-beta1 and beta3 selective inhibitor: results of a phase 1 monotherapy dose escalation study in solid tumors and evidence of target engagement in patients

Journal for ImmunoTherapy of Cancer ◽

10.1136/lba2019.10 ◽

2020 ◽

Vol 8 (Suppl 1) ◽

pp. A6.2-A7 ◽

Cited By ~ 1

Author(s):

Timothy Yap ◽

Daniel Araujo ◽

Debra Wood ◽

Jean-François Denis ◽

Tina Gruosso ◽

...

Keyword(s):

Solid Tumors ◽

Immune Evasion ◽

Phase 1 ◽

Locally Advanced ◽

List Type ◽

Functional Evaluation ◽

Tgf Beta ◽

Link Type ◽

Skin Biopsies ◽

Dose Levels

BackgroundAVID200 is a rationally designed first-in-class receptor ectodomain trap that inhibits transforming growth factor-beta (TGF-beta) isoforms -beta1 and -beta3 with pM potency. TGF-beta signaling is highly immunosuppressive in the tumor microenvironment and has been associated with immune checkpoint inhibitor resistance.1-4 TGF-beta1 and -beta3 are most closely associated with cancer progression whereas TGF-beta2 is required for normal cardiac function and hematopoiesis. Accordingly, selective targeting of TGF-beta1 and -beta3 by AVID200 may improve the efficacy of immunotherapy while avoiding toxicities associated with earlier generations of non-selective TGF-beta inhibitors.MethodsThis open-label, multicenter Phase 1 study (NCT03834662) evaluated safety, tolerability and dose-limiting toxicities (DLTs) of sequential escalating doses of AVID200 (Q3W IV) to establish the recommended Phase 2 dose. Patients with documented, locally advanced or metastatic solid tumors without other treatment options were eligible. The primary objective was safety and tolerability; secondary objectives included preliminary anti-tumor activity, pharmacokinetics (PK), and assessment of pharmacodynamic biomarkers indicative of target modulation. PK was assessed by enzyme immunoassay. Ability of AVID200 to selectively sequester and neutralize its target was assessed by TGF-beta quantification per ELISA, as well as cell-based IL-11 release functional evaluation of TGF-beta signal inhibition. In addition, phosphorylation of SMAD2, a downstream target of TGF-beta, was assessed by immunohistochemistry in skin biopsies at screening and Cycle 1, Day 4 (C1D4).ResultsEnrollment to all planned cohorts is complete: A total of 13 patients with ECOG 0-1 received AVID200 across the three planned dose levels of 180 (N=7), 550 (N=3), and 1100 mg/m2 (N=3) (~5, 15, and 30 mg/kg). The MTD was not reached. Grade 3 study drug-related AEs were reported in two patients (diarrhea, lipase elevation); no related Grade 4 or 5 AEs were observed. Serum exposure was dose-proportional. AVID200 sequestered circulating endogenous active TGF-beta at all dose levels. Moreover, AVID200 in patient plasma potently neutralized TGF-beta1- and -3 – but not -beta2 – mediated signaling. SMAD2 phosphorylation in skin biopsies was detectably reduced at C1D4 across all dose levels. Three of nine patients evaluated for response had a best response of stable disease (SD), including one prolonged SD which was ongoing at six months at time of writing.ConclusionsAVID200 has been well tolerated as monotherapy and engaged its target in patients providing proof-of-principle that selective and potent inhibition of TGF-beta1 and -beta3 is feasible in the clinic. The results warrant evaluation of AVID200 in combination with anti-PD(L)1 and other anti-cancer therapies.AcknowledgementsWe would like to thank all participating patients, their families and caretakers as well as staff members at the clinical sites.Trial RegistrationClinicaltrials.gov NCT03834662Ethics ApprovalThe study was approved by START-Midwest‘s IRB (approval number STMW2018.19), University Health Network‘s Research Ethics Board (approval number 18-6104), and The University of Texas MD Anderson Cancer Center‘s IRB (approval number 2018-1079).ReferencesMariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554:544–548.Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun 2018; 9:4692.Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018; 554:538–543.Zhao F, Evans K, Xiao C, et al. Stromal Fibroblasts Mediate Anti–PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma. Cancer Immunol Res 2018; 6:1459–1471.

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711 HBM1022, a novel anti-CCR8 antibody depletes tumor-infiltrating regulatory T cells via enhanced ADCC activity, mediates potent anti-tumor activity with Keytruda

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0711 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A753-A753

Author(s):

Shuang Lu ◽

Shaoping Hu ◽

Xin Gan ◽

Yongqiang Wang ◽

Chuchu Zhao ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Treg Cells ◽

Functional Assay ◽

List Type ◽

Adcc Activity ◽

Dependent Cell ◽

Tumor Types

BackgroundCCR8-expressing CD4 and Foxp3 positive Treg (CCR8+ Treg) has been demonstrated to be a major driver for immunosuppression in solid tumors1 <1> Superscript. Clinical studies have shown that CCR8 is selectively up-regulated by tumor resident Tregs in several tumor types including clear cell renal cell carcinoma (ccRCC)2 <2> Superscript and breast cancer3 <3> Superscript. In these tumor types, CCR8 exhibit strong expression on tumor resident Tregs while it is rarely observed on Tregs in peripheral blood mononuclear cells (PBMCs). High expression of the CCR8 in tumor-infiltrating lymphocytes-Treg cells (TIL-Tregs) was associated with poor prognosis in breast cancer patients. These results suggest CCR8 as a promising therapeutic target; and anti-CCR8 mAbs could selectively inhibit a subpopulation of tumor resident Tregs in the tumor microenvironment (TME), to augment antitumor immunity.MethodsIn vitro assay:HBM1022 binding on human, cynomolgus CCR8 and TIL-Tregs are evaluated via flow cytometry. Blocking and ADCC functional assay are all based on CCR8 overexpressing cell lines.In vivo efficacy study:HBM1022 anti-CCR8 antibody was administered after implantation (≈ 100 mm3 <3>Superscript tumor volume) alone and in combination with anti−PD-1.ResultsAnti-CCR8 antibody HBM1022 specifically binds to cell lines that over-express human or cynomolgus CCR8, as well as TIL-Tregs in multiple cancer types with the high affinity. HBM1022 potently blocks CCL1 binding to both human and cynomolgus CCR8. HBM1022 inhibits CCL1-induced migration and related GPCR signaling pathways. Furthermore, with enhanced antibody-dependent cell-mediated cytotoxicity (eADCC) activity, HBM1022 exhibits potent in vitro killing activity on CCR8-expressing cells. HBM1022 shows tumor growth inhibition as monotherapy in preclinical mouse syngeneic and humanized models. Moreover, HBM1022 shows enhanced antitumor activity with the combination of Keytruda® in preclinical efficacy models.ConclusionsOur finding reveals HBM1022 as an innovative immunotherapy targeting intra-tumoral suppressive Treg cells to change suppressive tumor to hot tumor. HBM1022 presents its great potential as exciting mono or combo anti-tumor therapies.ReferencesYiftah B, Gizi W, Eran L, et al. CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A 2017;114 (23):6086–6091.Tetsuya Y, Yujiro K, Mitsunobu M, et al. Method of treating cancer with an anti-CCR8 having antibody-dependent cell-mediated cytotoxicity (ADCC) activity against cells expressing CCR8. US10550191B2. 2020.George P, Catherine K, Kenmin W, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 2016;45:1122–1134.

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373 Phase 1/2 study of subcutaneously administered ALKS 4230, a novel engineered cytokine, as monotherapy and in combination with pembrolizumab, in patients with advanced solid tumors: ARTISTRY-2

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0373 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A398-A398

Author(s):

John Powderly ◽

Bradley Carthon ◽

Marc Ernstoff ◽

Anthony Olszanski ◽

John Wrangle ◽

...

Keyword(s):

T Cells ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Colonic Obstruction ◽

Systemic Exposure ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Advanced Solid Tumors ◽

Link Type

BackgroundALKS 4230 is a novel engineered cytokine designed to selectively bind and activate the intermediate affinity IL-2 receptor. Intravenous (IV) dosing of ALKS 4230 has shown encouraging efficacy and acceptable tolerability, as monotherapy and in combination with pembrolizumab, in patients with advanced solid tumors (ARTISTRY-1, NCT02799095). Subcutaneous (SC) dosing may be preferable to IV in certain clinical situations.MethodsARTISTRY-2 (NCT03861793) is an ongoing phase 1/2 study of SC ALKS 4230 ± pembrolizumab. In phase 1, cohort-specific doses of SC ALKS 4230 are administered on either an every-7-day (q7d) or every-21-day (q21d) schedule during a 6-week lead-in period, followed by combination with IV pembrolizumab 200 mg q21d. Each patient assigned to a given cohort receives ALKS 4230 at a single dose level and on a schedule of either q7d or q21d. Safety, tolerability, dose-limiting toxicities (DLTs), and pharmacokinetics/pharmacodynamics from dose escalation, as of 7/24/2020 are reported in this abstract.Results38 patients have been treated with ALKS 4230 across 7 assigned cohorts, with SC doses ranging from 0.3 mg to 10 mg (median age, 61.5 [28–82] years; median number of prior therapies 4 [0–17]; 45% were previously treated with immunotherapy). 25 patients completed monotherapy and initiated combination therapy. Median duration of treatment was 64.5 (1–506) days. Systemic exposure to ALKS 4230 increased with increasing dose, resulting in a dose dependent increase in circulating natural killer and CD8+ T cells, without significant impact on regulatory T cells. Overall, adverse events (AEs), regardless of causality, occurred in 33 (86.8%) patients. Treatment-related AEs (TRAEs; investigator assessed) occurred in 32 (84.2%) patients, and the most common TRAEs are presented in table 1. One patient experienced a serious TRAE, a grade 3 tumor flare manifesting as colonic obstruction. The maximum tolerated dose as well as recommended phase 2 dose for SC administration has not yet been determined.Abstract 373 Table 1Most common (≥20%) TRAEs overall and by dose schedule (by investigator assessment)ConclusionsALKS 4230 is a promising investigational agent for the treatment of advanced solid tumors. The SC safety profile is consistent with the known and anticipated pharmacologic effects of ALKS 4230. Consistent with IV dosing, SC administration of ALKS 4230 q7d or q21d maintained the desired immune responses as demonstrated by pharmacodynamic outcomes. Potentially lower rates of fever and chills observed, relative to IV dosing, are presumed to be consistent with lower peak concentrations achieved so far via the SC route. The study, including dose escalation, is ongoing.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel and funded by Alkermes, Inc.Trial RegistrationClinicalTrials. gov NCT03861793Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites; IRB reference numbers 20182543 (Western IRB), 00006731 (Roswell Park Comprehensive Cancer Center), STUDY00000056 (Georgetown University, MedStar Health Research Institute).

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417 Design and rationale of a phase 1 study evaluating AMG 256, a novel, targeted, IL-21 receptor agonist and anti-PD-1 antibody, in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0417 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A443-A443

Author(s):

Gregory Durm ◽

Sophia Frentzas ◽

Erik Rasmussen ◽

Saltanat Najmi ◽

Nooshin Sadraei

Keyword(s):

Solid Tumors ◽

Tumor Immunity ◽

Renal Cell ◽

Phase 1 ◽

List Type ◽

Solid Organ ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Drug Study ◽

Interleukin 21

BackgroundCheckpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance.1 The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer.2 IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models.3 4 AMG 256 is a mutated IL-21 cytokine fused to an anti-PD-1 antibody to combine IL-21 pathway stimulation with checkpoint inhibition—a strategy that is designed to prime and extend the activity of cytotoxic and memory T cells and induce anti-tumor immunity. This first-in-human (FIH) study will assess safety, tolerability, and estimated dosing of AMG 256 monotherapy in patients with advanced solid tumors.MethodsThis is a FIH, multicenter, non-randomized, open-label, phase 1 study (NCT04362748) of AMG 256 in patients with advanced solid tumors. The planned sample size is approximately 100 patients in two parts: part 1 will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD), part 2 will evaluate the MTD determined in part 1 to further characterize the safety profile and preliminary tumor response. AMG 256 will be delivered by intravenous (IV) infusion. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status ≤ 2, histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation, and at least one measurable lesion ≥ 10 mm that has not undergone biopsy within 3 months of screening scan. Exclusion criteria include primary brain tumor, untreated or symptomatic brain metastases, currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study, history of solid organ transplantation or major surgery within 28 days of study day 1, live vaccine therapy within 4 weeks prior to study day 1, and active infection requiring oral or IV therapy. The primary endpoints are incidence of dose-limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity (objective response, duration of response, progression-free survival, disease control rate, duration of stable disease, overall survival), and immunogenicity of AMG 256 via incidence of anti-AMG 256 antibodies.ResultsN/AConclusionsN/AAcknowledgements• The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.).Trial RegistrationNCT04362748Ethics ApprovalThe study was approved by all institutional ethics boards.ReferencesKluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer 2020;8:e000398.Thompson JA, Curti BD, Redman BG, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008;26:2034–2039.Lewis KE, Selby MJ, Masters G, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology. 2017;7:e1377873.Shen S, Sckisel G, Sahoo A, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol 2020;11:832.

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