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

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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368 Consistent pattern of immune activation induced by oncolytic adenovirus ONCOS-102 across diverse types of solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.368 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A396-A396

Author(s):

Lukasz Kuryk ◽

Anne-Sophie Moller ◽

Sandeep Kumar ◽

Alexander Shoushtari ◽

Luis Paz Ares ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Solid Tumors ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Clinical Importance ◽

Oncolytic Adenovirus ◽

Link Type ◽

Tumor Types

BackgroundSolid tumors exhibit highly variable compositions of immune infiltrates. Therapeutic compounds driving uniform remodeling of tumor microenvironment (TME) across tumor types may improve the efficacy of cancer immunotherapy. ONCOS-102, a granulocyte-macrophage colony stimulating factor (GM-CSF)-expressing oncolytic adenovirus (Ad5/3-D24-GMCSF), was tested for its safety, therapeutic efficacy and capacity to remodel TME in recently completed phase I/II clinical studies in anti-PD-1 refractory melanoma (NCT03003676) and malignant pleural mesothelioma (MPM) (NCT02879669).MethodsBiopsies were obtained from tumor lesions of patients treated with intra-tumoral injections of ONCOS-102 in combination with chemotherapy or pembrolizumab for MPM and melanoma, respectively. Tumor immune infiltrates were analyzed by immunohistology using several antibody panels. On-treatment biopsies were compared to paired baseline samples as wells as to samples from control patients treated with chemotherapy alone in the case of MPM. Gene expression data obtained by next generation RNA sequencing were used to complement the immunohistology analysis and all results were correlated to clinical outcomes.ResultsComparative TME analysis of anti-PD-1 refractory melanoma and MPM tumors revealed noticeably lower baseline T-cell infiltration in mesothelioma. Thus, fractions of CD8+ T-cells were significantly below 10% in 80% of MPM biopsies while approaching or exceeding this level in 60% of melanoma baseline samples. Comparison of tumor biopsies obtained at baseline or on-treatment, demonstrated increased infiltration by both CD4+ and CD8+ T-cells in large proportions of melanoma (CD4+: 13/20 (65%); CD8+: 16/19 (84%) and MPM (CD4+: 10/15 (67%); CD8+: 9/15 (60%) tumor lesions in response to ONCOS-102. Frequencies of cytotoxic T-cells with high granzyme-B expression also increased in response to the treatment in both tumor types, in particular when assessed as percentage of total CD8+ T-cells. Other observed changes induced by ONCOS-102 in samples taken from CR, PR and SD patients with MPM or melanoma included increased CD8/Treg ratio and modulation of PD-L1 expression. Biological and clinical importance of these findings was further supported by correlation between modulation of several subsets of genes related to the process of T-cell activation, such as cytotoxic granule components and co-stimulatory molecules, and clinical response to ONCOS-102 in melanoma and both tumor response and overall survival in MPM patients.ConclusionsONCOS-102 drives pro-inflammatory modulation of immune TME across tumor types of different origins, anatomical locations and immunological baseline characteristics. Our data support potential of ONCOS-102 to serve as a potent immune sensitizing agent in combination therapies with various classes of immunomodulatory compounds and chemotherapy.

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.861 ◽

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.

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Solid Tumor Microenvironment Can Harbor and Support Functional Properties of Memory T Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.706150 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peter M. Sullivan ◽

Steven James Reed ◽

Vandana Kalia ◽

Surojit Sarkar

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Solid Tumors ◽

Cd8 T Cells ◽

Solid Tumor ◽

Memory T Cells ◽

T Cell Responses ◽

Antigenic Stimulation ◽

Cell Responses

Robust T cell responses are crucial for effective anti-tumor responses and often dictate patient survival. However, in the context of solid tumors, both endogenous T cell responses and current adoptive T cell therapies are impeded by the immunosuppressive tumor microenvironment (TME). A multitude of inhibitory signals, suppressive immune cells, metabolites, hypoxic conditions and limiting nutrients are believed to render the TME non-conducive to sustaining productive T cell responses. In this study we conducted an in-depth phenotypic and functional comparison of tumor-specific T cells and tumor-nonspecific bystander memory T cells within the same TME. Using two distinct TCR transgenic and solid-tumor models, our data demonstrate that despite exposure to the same cell-extrinsic factors of the TME, the tumor-nonspecific bystander CD8 T cells retain the complete panoply of memory markers, and do not share the same exhaustive phenotype as tumor-reactive T cells. Compared to tumor-specific T cells, bystander memory CD8 T cells in the TME also retain functional effector cytokine production capabilities in response to ex vivo cognate antigenic stimulation. Consistent with these results, bystander memory T cells isolated from tumors showed enhanced recall responses to secondary bacterial challenge in a T cell transplant model. Importantly, the tumor-resident bystander memory cells could also efficiently utilize the available resources within the TME to elaborate in situ recall effector functions following intra-tumoral peptide antigen injection. Additionally, CRISPR-Cas9 gene deletion studies showed that CXCR3 was critical for the trafficking of both tumor antigen-specific and bystander memory T cells to solid tumors. Collectively, these findings that T cells can persist and retain their functionality in distinct solid tumor environments in the absence of cognate antigenic stimulation, support the notion that persistent antigenic signaling is the central driver of T cell exhaustion within the TME. These studies bear implications for programming more efficacious TCR- and CAR-T cells with augmented therapeutic efficacy and longevity through regulation of antigen and chemokine receptors.

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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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CXCR6 by increasing retention of memory CD8+ T cells in the ovarian tumor microenvironment promotes immunosurveillance and control of ovarian cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003329 ◽

2021 ◽

Vol 9 (10) ◽

pp. e003329

Author(s):

Ravikumar Muthuswamy ◽

AJ Robert McGray ◽

Sebastiano Battaglia ◽

Wenjun He ◽

Anthony Miliotto ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Cd8 T Cells ◽

Ovarian Tumor ◽

Critical Role ◽

Peripheral Tissues ◽

Memory Cd8 T Cells ◽

Tumor Tissues ◽

And Control

PurposeResident memory CD8 T cells, owing to their ability to reside and persist in peripheral tissues, impart adaptive sentinel activity and amplify local immune response, and have beneficial implications for tumor surveillance and control. The current study aimed to clarify the less known chemotactic mechanisms that govern the localization, retention, and residency of memory CD8 T cells in the ovarian tumor microenvironment.Experimental designRNA and protein expressions of chemokine receptors in CD8+ resident memory T cells in human ovarian tumor-infiltrating CD8+ T cells and their association with survival were analyzed. The role of CXCR6 on antitumor T cells was investigated using prophylactic vaccine models in murine ovarian cancer.ResultsChemokine receptor profiling of CD8+CD103+ resident memory tumor-infiltrating lymphocytes in patients with ovarian cancer revealed high expression of CXCR6. Analysis of The Cancer Genome Atlas (TCGA) (ovarian cancer database revealed CXCR6 to be associated with CD103 and increased patient survival. Functional studies in mouse models of ovarian cancer revealed that CXCR6 is a marker of resident, but not circulatory, tumor-specific memory CD8+ T cells. CXCR6-deficient tumor-specific CD8+ T cells showed reduced retention in tumor tissues, leading to diminished resident memory responses and poor control of ovarian cancer.ConclusionsCXCR6, by promoting retention in tumor tissues, serves a critical role in resident memory T cell-mediated immunosurveillance and control of ovarian cancer. Future studies warrant exploiting CXCR6 to promote resident memory responses in cancers.

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Inhibiting WNT Ligand Production for Improved Immune Recognition in the Ovarian Tumor Microenvironment

Cancers ◽

10.3390/cancers12030766 ◽

2020 ◽

Vol 12 (3) ◽

pp. 766 ◽

Cited By ~ 3

Author(s):

Whitney N. Goldsberry ◽

Selene Meza-Perez ◽

Angelina I. Londoño ◽

Ashwini A. Katre ◽

Bryan T. Mott ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Cd8 T Cells ◽

Ovarian Cancer Cell Line ◽

Immune Recognition ◽

Clinical Model ◽

Cell Functions

In ovarian cancer, upregulation of the Wnt/β–catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt pathway in a syngeneic ovarian cancer murine model could create a more T-cell-inflamed TME, which would lead to decreased tumor growth and improved survival. We preformed RNA sequencing in a cohort of human high grade serous ovarian carcinoma subjects. We used CGX1321, an inhibitor to the porcupine (PORCN) enzyme that is necessary for secretion of WNT ligand, in mice with established ID8 tumors, a murine ovarian cancer cell line. In order to investigate the effect of decreased Wnt/β–catenin pathway activity in the dendritic cells (DCs), we injected ID8 cells in mice that lacked β–catenin specifically in DCs. Furthermore, to understand how much the effects of blocking the Wnt/β–catenin pathway are dependent on CD8+ T cells, we injected ID8 cells into mice with CD8+ T cell depletion. We confirmed a negative correlation between Wnt activity and T cell signature in our cohort. Decreasing WNT ligand production resulted in increases in T cell, macrophage and dendritic cell functions, decreased tumor burden and improved survival. Reduced tumor growth was found in mice that lacked β–catenin specifically in DCs. When CD8+ T cells were depleted, CGX1321 treatment did not have the same magnitude of effect on tumor growth. Our investigation confirmed an increase in Wnt activity correlated with a decreased T-cell-inflamed environment; a relationship that was further supported in our pre-clinical model that suggests inhibiting the Wnt/β–catenin pathway was associated with decreased tumor growth and improved survival via a partial dependence on CD8+ T cells.

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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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