Agonistic CD40 Monoclonal Antibody Research Articles

TRLS-06. PHASE 1 STUDY OF THE CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M (SOTIGALIMAB) IN PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH RECURRENT OR PROGRESSIVE CNS TUMORS AND NEWLY DIAGNOSED BRAIN STEM GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC-051; NCT03389802)

Abstract BACKGROUND CD40 is a co-stimulatory receptor present on antigen-presenting cells. CD40 agonists are hypothesized to reverse cancer-induced immune suppression and induce tumor cell killing. The PBTC completed a first-in-pediatrics phase 1 study (PBTC-051) of the CD40 agonistic monoclonal antibody APX005M (sotigalimab). METHODS Patients 1-21.99 years old with recurrent/progressive/refractory malignant non-brainstem central nervous system (CNS) tumors were eligible for stratum 1, and those with post-radiation pre-progression diffuse intrinsic pontine glioma (DIPG) for stratum 2. Patients received APX005M (sotigalimab) via IV on day 1 of each 21 day cycle. A 3 + 3 statistical design was used for dose escalation through 3 planned dose levels (DL). Patients could receive APX005M (sotigalimab) for 36 cycles or until disease progression, unacceptable toxicity, or death. RESULTS 31 eligible patients enrolled (20 on stratum 1, 11 on stratum 2) between 2018-2023; 29 were evaluable for dose finding. The most common diagnosis in stratum 1 was ependymoma (35%). DL3 (0.6 mg/kg) was the recommended phase 2 dose (RP2D) for stratum 1 and DL2 (0.3 mg/kg) for stratum 2. Five patients had dose limiting toxicities—two stratum 1 patients at DL3 and three stratum 2 patients at DL3. The most common grade 3+ adverse events at least possibly attributable to APX005M (sotigalimab) were lymphopenia, neutropenia, leukopenia, and increased ALT. Median number of cycles was 2 (1-36) for stratum 1 and 3 (1-19) for stratum 2. No patients had an objective response to APX005M. 6 month progression-free survival (PFS) for stratum 2 patients (calculated from start of treatment) was 30.7±12.8%; median PFS was 3.7 months. CONCLUSIONS APX005M was well-tolerated in pediatric patients with both recurrent/refractory/progressive CNS tumors and post-radiation pre-progression DIPG. A RP2D was established for both populations. Future studies of this agent in pediatric neuro-oncology patients should prioritize combination therapy.

Abstract PO1-19-08: Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer

Abstract Background: Only a subset of patients with metastatic triple-negative breast cancers (TNBC) demonstrate response to FDA approved PD-1 immune checkpoint blockade (ICB), and few have durable responses. Data suggests that breast cancers have defects in antigen presentation and that antigen presenting cells especially the cDC1 subtype of dendritic cells (DCs) are required for response to ICB. CD40 agonists activate antigen presenting cells including DCs and B cells and repolarize macrophages to an anti-tumor phenotype. Flt3 ligand is a growth factor that increases differentiation and expansion of DCs. We recently demonstrated in pre-clinical TNBC models that the combination of liposomal doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal doxorubicin, CDX-1140 (CD40 agonist monoclonal antibody), and CDX-301 (recombinant Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic TNBC. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, or liposomal doxorubicin only) for one cycle prior to receiving triplet therapy with tissue biopsies done before and after the lead-in treatment. CDX-301 will be given for only two cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase II dose based on treatment-related adverse events and dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV TNBC (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line treatment for metastatic disease (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites (NCT05029999) and is currently open at University of Texas Southwestern Medical Center, Texas Oncology, University of Chicago, University of Texas San Antonio, Sarah Cannon Research Institute, and Johns Hopkins. Citation Format: Sangeetha Reddy, Joyce O'Shaughnessy, Navid Sadeghi, Samira Syed, Cesar Santa-Maria, Virginia Kaklamani, Nan Chen, Denise Yardley, Yisheng Fang, Isaac Chan, Nisha Unni, Sarah Kashanian, Namrata Peswani, Shahbano Shakeel, Meredith Carter, Kelly Kyle, Farjana Fattah, Chul Ahn, Ina Patel, Joshua Gruber, Dawn Klemow, Glenda Delgado, Nicole Sinclair, Michael Yellin, Heather McArthur, Rita Nanda, Suzanne Conzen, Carlos Arteaga. Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-08.

Nanofluidic delivery implant sustains localization and maximizes efficacy of intratumoral immunotherapy

Intratumoral immunotherapy holds promise for improving cancer treatment efficacy. However, rapid clearance from the tumor upon bolus volume injections limits efficacy and impedes assessment of dose-dependent effects on the tumor immune microenvironment (TIME). To this end, we developed a drug-agnostic nanofluidic implant to deliver immunotherapy within the tumor, providing a mechanism for sustained and controlled intratumoral dosing. Diffusive drug elution from the implant reservoir is controlled by a nanofluidic membrane, which abrogates rapid drug elimination from the tumor and maximizes immunotherapy localization. Here we first achieve in vitro sustained release of agonist CD40 monoclonal antibody (mAb), anti-programmed death ligand-1 (PDL1) mAb, and immune-cell targeted polymeric prodrugs of Resiquimod (toll-like receptor 7/8,TLR 7/8) and a small molecule STING agonist. We then demonstrated in vivo sustained intratumoral drug localization of agonist CD40 Ab and anti-PDL1 Ab in the 4T1 murine model of triple-negative breast cancer (TNBC). Further, we show highly effective anti-tumor efficacy with radiation therapy and sustained intratumoral co-delivery of agonist CD40 Ab and anti-PDL1 Ab in the EMT6 TNBC murine model. Finally, we demonstrate the versatility of this implant by showing that sustained intratumoral delivery of the STING or Resiquimod polymeric prodrugs strongly inhibits 4T1 tumor growth. Collectively, these results support our nanofluidic system as a therapeutic platform technology to investigate sustained intratumoral dosing of immunotherapy.

Machine Learning Links T-cell Function and Spatial Localization to Neoadjuvant Immunotherapy and Clinical Outcome in Pancreatic Cancer.

Tumor molecular data sets are becoming increasingly complex, making it nearly impossible for humans alone to effectively analyze them. Here, we demonstrate the power of using machine learning (ML) to analyze a single-cell, spatial, and highly multiplexed proteomic data set from human pancreatic cancer and reveal underlying biological mechanisms that may contribute to clinical outcomes. We designed a multiplex immunohistochemistry antibody panel to compare T-cell functionality and spatial localization in resected tumors from treatment-naïve patients with localized pancreatic ductal adenocarcinoma (PDAC) with resected tumors from a second cohort of patients treated with neoadjuvant agonistic CD40 (anti-CD40) monoclonal antibody therapy. In total, nearly 2.5 million cells from 306 tissue regions collected from 29 patients across both cohorts were assayed, and over 1,000 tumor microenvironment (TME) features were quantified. We then trained ML models to accurately predict anti-CD40 treatment status and disease-free survival (DFS) following anti-CD40 therapy based on TME features. Through downstream interpretation of the ML models' predictions, we found anti-CD40 therapy reduced canonical aspects of T-cell exhaustion within the TME, as compared with treatment-naïve TMEs. Using automated clustering approaches, we found improved DFS following anti-CD40 therapy correlated with an increased presence of CD44+CD4+ Th1 cells located specifically within cellular neighborhoods characterized by increased T-cell proliferation, antigen experience, and cytotoxicity in immune aggregates. Overall, our results demonstrate the utility of ML in molecular cancer immunology applications, highlight the impact of anti-CD40 therapy on T cells within the TME, and identify potential candidate biomarkers of DFS for anti-CD40-treated patients with PDAC.

Cell targeting and immunostimulatory properties of a novel Fcγ-receptor-independent agonistic anti-CD40 antibody in rhesus macaques

Targeting CD40 by agonistic antibodies used as vaccine adjuvants or for cancer immunotherapy is a strategy to stimulate immune responses. The majority of studied agonistic anti-human CD40 antibodies require crosslinking of their Fc region to inhibitory FcγRIIb to induce immune stimulation although this has been associated with toxicity in previous studies. Here we introduce an agonistic anti-human CD40 monoclonal IgG1 antibody (MAB273) unique in its specificity to the CD40L binding site of CD40 but devoid of Fcγ-receptor binding. We demonstrate rapid binding of MAB273 to B cells and dendritic cells resulting in activation in vitro on human cells and in vivo in rhesus macaques. Dissemination of fluorescently labeled MAB273 after subcutaneous administration was found predominantly at the site of injection and specific draining lymph nodes. Phenotypic cell differentiation and upregulation of genes associated with immune activation were found in the targeted tissues. Antigen-specific T cell responses were enhanced by MAB273 when given in a prime-boost regimen and for boosting low preexisting responses. MAB273 may therefore be a promising immunostimulatory adjuvant that warrants future testing for therapeutic and prophylactic vaccination strategies.

A phase II trial with safety lead-in to evaluate the addition of sotigalimab, a CD40 agonistic monoclonal antibody, to standard-of-care doxorubicin for the treatment of advanced sarcoma.

11565 Background: Immune checkpoint inhibitors have limited efficacy in soft tissue sarcoma (STS) due to insufficient T-cell activation and infiltration by immunosuppressive macrophages. Sotigalimab (S), a high-affinity humanized monoclonal antibody for CD40, promotes antigen presentation, stimulates T-cell responses, and reprograms immunosuppressive macrophages. Preclinical studies with CD40 agonists revealed efficacy in immune “cold” tumor types and synergy with chemotherapy. Standard first-line doxorubicin (D) provides objective response rate (ORR) < 15% and median progression free survival (mPFS) of 4-6 mos in advanced STS. We therefore conducted this first-in-human study of D+S in STS. Methods: An open-label, single-arm, multi-center, phase 2 study evaluated D+S in advanced STS. Pts had ECOG PS ≤ 1 and any number of prior lines (but were anthracycline-naïve). The study initially enrolled all STS subtypes (except KS and GIST) but was amended in 12/2020 to limit enrollment to dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), and undifferentiated pleomorphic sarcoma (UPS). Pts received D 75 mg/m2 IV D1 + S 0.3 mg/kg IV D1 for eight 21-day cycles, followed by S monotherapy. A safety lead-in was performed (first 6 patients). Primary endpoint was ORR. Secondary endpoints included PFS and safety. A Simon two-stage design was used. If ≥ 7/32 responded overall, the treatment would be considered promising (85% power, α = 0.05). A subset of patients underwent paired tumor biopsies. Results: 32 pts have enrolled (median age 62; 10 LMS, 10 UPS, 9 DDLPS, 3 other). 4 pts remain on treatment with median follow-up of 2.8 mos (1 UPS pt has not reached first imaging). D (75 mg/m2) + S (0.3 mg/kg) was safe and tolerable without dose limiting toxicity. Overall ORR was 16% (5/31). Objective responses occurred in UPS (2), LMS (1), other LPS (1), and epithelioid hemangioendothelioma (1). Overall mPFS was 7.5 mos (95% CI 5.6-14.9 mos) and PFS rate at 6 and 12-mos was 55% and 31%, respectively. mPFS by STS subtype was 11.9 mos (95% CI: 10.3 – NE) for DDLPS, 7.5 mos (95% CI: 1.4—NE) for UPS and 5.6 mos (95% CI: 1.3 – NE) for LMS. Overall, 17/31 (55%) pts experienced grade 3 or 4 adverse events (AEs): most commonly, neutropenia (32%), febrile neutropenia (19%), and anemia (16%). 16% of pts experienced cytokine release (all low-grade). Correlative analysis of biopsies with high-definition spatial proteomics is ongoing. Conclusions: D (75 mg/m2) + S (0.3 mg/kg) every 21 days is safe and tolerable in STS. Final analysis of the primary endpoint awaits further follow-up on recently enrolled patients. Subtype-specific analysis suggests improvement in median PFS for DDLPS over historical controls: 11.9 mos vs 4 mos (Stacchiotti S. Ann Oncol 2020; Livingston M. Sci Rep 2017). An expansion of the DDLPS cohort is planned. Clinical trial information: NCT03719430 .

A phase 1b, open-label, two-part safety, tolerability, and efficacy study of a soluble beta-glucan (odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma whose disease did not progress during first-line (1L) chemotherapy.

TPS4201 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a 5-year overall survival (OS) rate of 3%. Standard of care treatment is continuous cytotoxic chemotherapy which produces modest improvements in OS but is also associated with significant toxicity raising the need for novel treatment paradigms. Although immunotherapy has yet to produce clinical benefit for most patients with PDAC, preclinical modeling demonstrates its potential and show that combinations of myeloid agonists can trigger robust synergistic anti-tumor activity against PDAC tumors that are otherwise resistant to immunotherapy including immune checkpoint blockade (anti-CTLA4, anti-PD1). In this study, odetiglucan (OD), a novel beta glucan pathogen associated molecular pattern (PAMP), will be combined for the first time with CDX-1140, a fully human Ig2K agonistic monoclonal CD40 antibody in the maintenance setting after an induction phase of cytotoxic chemotherapy. OD and a CD40 agonist directly promote the activation and maturation of antigen presenting cells and shift the suppressive TME to enhance T-cell responses through non-redundant myeloid signaling pathways. We hypothesize that the combination of OD and CD40 agonist therapy has the potential to trigger anti-tumor immunity in PDAC and thus, extend and deepen responses to 1L cytotoxic chemotherapy. Methods: A two-part Phase 1b study of metastatic PDAC pts who have evidence of response or stable disease following 16-24 wks of chemotherapy is being conducted. Part A uses a 3+3 design; pts will receive OD 4 mg/kg QW + CDX-1140 1.5 mg/kg Q3W. Following a dose-limiting toxicity observation period, the dose will be held at 1.5 mg/kg or decreased to 0.72 mg/kg Q3W. Once preliminary safety is established, the cohort will be expanded to 15 pts. Part B pts will receive OD 4mg/kg + CDX-1140 at the dose identified in Part A Q3W. The study will enroll 30 pts. Main eligibility criteria: Metastatic PDAC having durable stable disease or response to 1L chemotherapy; serum ABA ≥20 µg/mL, and no prior anti-CD40 mAb or immunomodulatory treatment exposure. Primary endpoints are MTD, RP2D, and safety. Secondary endpoints include DOR, PFS, ORR, and OS and exploratory endpoints include evaluating immune pharmacodynamic responses in peripheral blood and tumor. Safety parameters will be listed and summarized using descriptive statistics. ORR will be tabulated by overall frequency; DOR, TTF, PFS and OS will be summarized and presented using Kaplan-Meier and waterfall plots. 5 US sites will participate. Clinical trial information: NCT04834778 .

537 OPTIMIZE-1, an open-label phase 1b/2 study assessing the safety and efficacy of mitazalimab in combination with chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma

BackgroundMitazalimab is a human CD40 agonistic antibody (IgG1) developed for cancer immunotherapy. Targeting CD40 provides an opportunity to kickstart the cancer-immunity cycle by priming and activating tumor-specific T cells.1 2 Furthermore, the effects of CD40 agonists on myeloid cells promote degradation of the tumor stroma, improving the influx of T cells and chemotherapeutic agents into the tumor.1 Targeting CD40 with mitazalimab in pancreatic ductal adenocarcinoma (PDAC), which is defined by a desmoplastic tumor stroma that hosts immune-suppressive macrophages, has the potential to augment responses to chemotherapy, initiating an effective anti-tumor immune response. Data from a phase 1 study (NCT02829099) demonstrated early signs of clinical activity in solid tumors with one partial response and SD in 37% of the patients.3 Mitazalimab was safe and tolerable at intravenous doses up to 1200 μg/kg and most drug-related adverse events were grade 1 or 2.3 Biomarker data from this study demonstrated proof of mechanism, validating mitazalimab’s ability to activate CD40 in cancer patients. In preclinical hCD40tg mouse models, repeated administration of mitazalimab in combination with FOLFIRINOX induced a long-term survival when compared to chemotherapy alone.4MethodsOPTIMIZE-1 is a phase 1b/2, open-label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with chemotherapy (mFOLFIRINOX) in adults diagnosed with previously untreated metastatic PDAC. Mitazalimab and mFOLFIRINOX will be administered by intravenous infusions following a 14-day cycle schedule where mitazalimab will be administered 2 days after mFOLFIRINOX, except for the first cycle of 21 days where mitazalimab will be administered on Day 1 and 10 and infusion of mFOLFIRINOX will start Day 8. In Part 1 (Phase 1b) of the study, the dose of mitazalimab will be escalated from 450 µg/kg to 900 µg/kg (2 dose levels to be evaluated) to obtain the recommended phase 2 dose (RP2D). Part 1 follows a Bayesian optimal interval design (BOIN) with at least 3 patients enrolled at each dose level. A minimum of 6 patients will be evaluated at the RP2D. In Part 2 of the study, the RP2D of mitazalimab will be administered in combination with mFOLFIRINOX to all patients. The study expansion will evaluate the clinical efficacy of mitazalimab in combination with mFOLFIRINOX assessing objective response rate (ORR) (primary endpoint), Progression-free survival (PFS) and Overall survival (OS) (secondary endpoints). The study expansion includes a Simon’s two-stage design with an interim analysis to allow stopping for futility or efficacy based on ORR.Trial RegistrationNCT04888312ReferencesEnell Smith K, Deronic A, Hägerbrand K, Norlén P & Ellmark P. Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy. Expert Opinion on Biological Therapy 2021 Jun 17, 1–12.Ellmark P, Mangsbo SM, Furebring C, Totterman TH & Norlen P. Kick-starting the cancer-immunity cycle by targeting CD40. Oncoimmunology 2015;4:e1011484.Calvo E, et al. A phase I study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of JNJ-64457107, a CD40 agonistic monoclonal antibody, in patients (pts) with advanced solid tumors. Journal of Clinical Oncology 2019;37:2527–2527.Adnan Deronic MT, Anneli Nilsson, Peter Ellmark, Anette Fält, Karin Enell Smith. Mitazalimab, a potent CD40 agonist with potential for combination with chemotherapy. AACR Annual meeting Abstract 2021;1593.Ethics ApprovalThe study was approved 19 July 2021 by CHU UCL Namur, site Godinne Comité d’éthique Avenue Docteur G. Thérasse 1 5530 YVOIR, Belgium, approval number 32/2021and2 July 2021 by Comite de Protection des Personnes EST I, ‘France, approval number SI2G 21.00648.677157

CD40 Agonist Monoclonal Antibody-Mediated Hepatitis in TNF-Receptor 1 Gene Knockout Mice.

Tumor necrosis factor-alpha (TNF-α) plays an important role in liver inflammation. CD40-CD40 ligand (CD40-CD40L) is a key receptor–ligand signaling pair involved in the adaptive immune response and pathogenesis of autoimmune diseases. In mice, CD40 activation leads to sickness behavior syndrome (SBS) comprising weight loss, sleep disruption and depression, which can be blocked by administration of the TNF-inhibitor etanercept. In the present study, we assessed the extent of hepatic inflammation in mice devoid of the TNF-receptor 1 (TNFR1)-mediated signaling pathway. The TNFR1-depleted (TNFR1−/−) adult mice and their wild type littermates were given a single intra-peritoneal injection of CD40 agonist monoclonal antibody (mAb) or rat IgG2a isotope control. As described previously, TNFR1−/− mice were protected from SBS upon CD40 mAb treatment. Cd40, tnf and tnfr1 mRNA and Tnf-α peptide were increased in the liver of CD40 mAb-stimulated wild type mice. Serum alanine aminotransferase was elevated in both CD40-activated wild type and TNFR1−/− mice. TNFR1−/− mice showed much less intra-parenchymal infiltrates, hepatocellular necrosis, and perivascular clusters upon CD40 mAb activation than their wild type littermates. A gene expression microarray detected increased activity of metabolic and detoxification pathways and decreased activity of inflammatory pathways. We conclude that immune activation and development of liver inflammation in CD40L interactions depend on TNFR1-mediated signaling pathways and are counteracted by alterations in metabolic pathways.

Co-Stimulatory versus Cell Death Aspects of Agonistic CD40 Monoclonal Antibody Selicrelumab in Chronic Lymphocytic Leukemia.

Simple SummaryPrevious observations have shown that CD40 activation of CLL cells via coculture with CD40L-expressing fibroblasts increases sensitivity to cell death by CD20 mAbs rituximab and obinutuzumab. We studied the activity of the fully human-agonistic CD40 mAb selicrelumab in primary CLL cells in relation to cell activation, induced pro-survival profile and sensitization for cell death by aCD20 mAbs. We found that the pro-survival effect of selicrelumab is minimal, while cell death by combined selicrelumab plus anti-CD20 antibody treatment is maintained. Thus, further investigation of applying selicrelumab combined with anti-CD20 mAbs in a therapeutic setting might be considered.Objectives: Chronic lymphocytic leukemia (CLL) is a common form of leukemia with a heterogeneous clinical course that remains incurable due to the development of therapy resistance. In lymph node proliferation centers, signals from the microenvironment such as CD40 ligation through interaction with follicular T helper cells shield CLL cells from apoptosis. Previous observations have shown that, despite CD40-induced changes in apoptotic mediators resulting in cell survival, CD40 activation also increases sensitivity to cell death by CD20 mAbs rituximab and obinutuzumab. To further investigate these observations, we here studied the activity of the fully human agonistic CD40 mAb selicrelumab in primary CLL cells in relation to cell activation, induced pro-survival profile, and sensitization for cell death by aCD20 mAbs, in vitro. Methods: CLL cells from peripheral blood were isolated by the Ficoll density method. The expression of activation markers and cytokine production following CD40 stimulation was quantified by flow cytometry and ELISA. The anti-apoptotic profile of CLL induced by stimulation was evaluated by the expression of BCL-2 proteins with Western blot, and resistance to venetoclax with flow cytometry. Cell death induced by the combination of selicrelumab and aCD20 mAbs was quantified by flow cytometry. Results: CLL cells treated with selicrelumab upregulated co-stimulatory molecules such as CD86, TNF-α and death receptor CD95/Fas. In contrast to the CD40 ligand-transfected NIH3T3 cells, induction of resistance to venetoclax by selicrelumab was very moderate. Importantly, selicrelumab stimulation positively sensitized CLL cells to CD20-induced cell death, comparable to CD40 ligand-transfected NIH3T3 cells. Conclusions: Taken together, these novel insights into selicrelumab-stimulatory effects in CLL may be considered for developing new therapeutic strategies, particularly in combination with obinutuzumab.

Gemcitabine (Gem) and nab-paclitaxel (NP) ± nivolumab (nivo) ± CD40 agonistic monoclonal antibody APX005M (sotigalimab), in patients (Pts) with untreated metastatic pancreatic adenocarcinoma (mPDAC): Phase (Ph) 2 final results.

4019 Background: Results from a ph1b trial evaluating gem/NP with CD40 agonistic monoclonal antibody APX005M ± nivo demonstrated promising clinical activity in pts with untreated mPDAC (O’Hara 2021). Herein, we report results from the follow-on, randomized (rand) ph2 trial evaluating gem/NP ± nivo ± APX005M. Methods: Pts with untreated mPDAC were rand to 1 of 3 open-label arms: gem/NP/nivo (A), gem/NP/APX005M (B), gem/NP/nivo/APX005M (C). All pts were treated with 1000 mg/m2 gem and 125 mg/m2 NP. Patients received 240 mg nivo in arms A and C and 0.3 mg/kg APX005M (RP2D) IV in arms B and C. Ph1b pts were included in ph2 analyses. 1° endpoint: 1-year OS rate of each arm, compared to a 35% historical OS rate for gem/NP (Von Hoff 2013). Key 2° endpoints: ORR, DCR, DOR, PFS and safety. Tumor and blood were collected for biomarker analysis. Planned enrollment of 35 pts/arm provided 81% power for testing the alternative of 58% OS rate vs 35%, using a 1-sided, 1-sample Z test with 5% type I error. Trial was not powered for cross-arm comparison. Results: 93 pts were rand in ph2 (N = 34, 30, 29 to A, B, C); when ph1b pts included, a total of 105 pts (34, 36, 35) were analyzed for efficacy and 108 pts (36, 37, 35) for safety. Min follow-up was 14 months (mos). Baseline characteristics were balanced across arms, inclusive of tumor burden, presence of liver metastases and stage at initial diagnosis (stage 1-3 vs 4). 1-year OS rate was 57% (1-sided p = 0.007 vs 35% historical rate, 95% lower CI bound = 41%) for A, 51% (p = 0.029, 95% bound = 36%) for B and 41% (p = 0.236, 95% bound = 27%) for C. Median OS and secondary endpoints are listed in Table. TRAE rates were similar across arms and to ph1b. 8 (7%) pts experienced an AE leading to tx discontinuation (6, 1, 1 in A, B, C), 40 (37%) pts experienced a serious TRAE (14, 15, 11 in A, B, C) and 2 pts died due to TRAEs; 1 each in B (acute hepatic failure) and C (intracranial hemorrhage). Conclusions: In this ongoing, seamless ph1b/2 trial of gem/NP ± nivo ± APX005M in pts with mPDAC, antitumor activity was observed in all arms. 1° endpoint of 1-year OS > 35% was met when combining gem/NP with either nivo or APX005M; however, not the combination. Safety was manageable; consistent with ph1b. Detailed multiomic immune and tumor biomarker analyses are underway to elucidate mechanisms of action and inform pt subsets that benefit most from these combinations. Clinical trial information: NCT03214250. [Table: see text]

Pre-clinical evaluation of immunoPET imaging using agonist CD40 monoclonal antibody in pancreatic tumor-bearing mice

BackgroundA novel [64Cu]Cu-NOTA-aCD40 immunoPET tracer was developed to image a CD40+ pancreatic tumor model in C57BL/6 mice and to study the biodistribution profile of the agonist CD40 (aCD40) monoclonal antibody (mAb) alone or combined with other mAbs. ProceduresCopper-64 ([64Cu]Cu) labeled NOTA-aCD40 and NOTA-IgG (10 μg; 7 MBq) were injected intravenously into C57BL/6 mice with subcutaneous mT4 tumors to assess specificity 48 h post injection (p.i.) through positron emission tomography/computed tomography (PET/CT) imaging and biodistribution studies (n = 5). [64Cu]Cu-NOTA-aCD40 was injected alone or simultaneously in combination with a therapeutic mass of cold aCD40 (100 μg), aPD-1 (200 μg) and aCTLA-4 (200 μg) mAbs. A group of mice with or without tumor received the second round of injections 1 or 3 weeks apart, respectively. PET/CT imaging and biodistribution studies were performed at 48 h p.i. The organ dose for [64Cu]Cu was estimated based on biodistribution studies with 2 μg [64Cu]Cu-NOTA-aCD40 (corresponds to 5 mg patient dose) in non-tumor bearing mice. Results[64Cu]Cu-NOTA-aCD40 accumulation was 2.3- and 7.8-fold higher than [64Cu]Cu-NOTA-IgG in tumors and spleen, respectively, indicating the specificity of aCD40 mAb in a mouse pancreatic tumor model. Tumor accumulation of [64Cu]Cu-NOTA-aCD40 was 21.2 ± 7.3%ID/g at 48 h after injection. Co-injection of [64Cu]Cu-NOTA-aCD40 with cold aCD40 mAb alone or with PD-1 and CTLA-4 mAbs reduced both spleen and tumor uptake, whereas liver uptake was increased. With the second round of injections, the liver was the only organ with substantial uptake. With a 2 μg administered dose of [64Cu]Cu-NOTA-aCD40 in a dosimetry study, the liver to spleen ratio was greater compared to the 10 μg dose (2.8 vs 0.37; respectively). The human equivalent for the highest dose organ (liver) was 198 ± 28.7 μSv/MBq. ConclusionsA CD40-immunoreactive [64Cu]Cu-NOTA-aCD40 probe was developed. The ratio of spleen to liver accumulation exceeded that of the IgG isotype and was greatest with a single small, injected mass. The safety of human patient imaging with [64Cu]Cu was established based on extrapolation of the organ specificity to human imaging.

APX005M, a CD40 monoclonal antibody, for patients with pancreatic adenocarcinoma.

Despite progress, chemotherapy yields disappointing results in metastatic pancreatic ductal adenocarcinoma and median overall survival is less than 12 months. Mark H O’Hara and colleagues1 investigated how to improve this figure by building on a nab-paclitaxel plus gemcitabine chemotherapy backbone in a phase 1b trial assessing the recommended phase 2 dose of the CD40 agonistic monoclonal antibody APX005M, with and without nivolumab, in an attempt to sensitise an immunologically cold disease. The authors provide an example of a smart strategic project of drug development and multicentre cooperation aimed at boosting and fostering the acquisition of sound and reliable data by rapid execution of a well designed and well managed trial.

EPCT-02. PBTC-051: FIRST IN PEDIATRICS PHASE 1 STUDY OF CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M IN PEDIATRIC SUBJECTS WITH RECURRENT/REFRACTORY BRAIN TUMORS

BACKGROUNDCD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors.RESULTSAccrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled.CONCLUSIONThe CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.

A phase II trial with safety lead-in to evaluate the addition of APX005M, a CD40 agonistic monoclonal antibody, to standard-of-care doxorubicin chemotherapy for the treatment of advanced soft tissue sarcoma.

TPS85 Background: Soft tissue sarcoma (STS) is a biologically heterogeneous disease for which existing immunotherapy approaches (e.g. anti-PD-1) have shown limited clinical activity. Cytotoxic chemotherapy with doxorubicin (D), an anthracycline, remains standard-of-care treatment for most advanced STS. Combining chemotherapy with immunomodulatory treatments may enhance antigen presentation and favorably impact the immune microenvironment (iME). APX005M (Apexigen; San Carlos, CA) is a novel CD40 agonistic antibody. Preclinically, CD40 ligation plus chemotherapy induced expression of costimulatory and major histocompatibility complex molecules on antigen presenting cells (APCs), shifted the myeloid compartment towards an M1 phenotype and expanded T-cell receptor clonality, which are characteristics in which the sarcoma iME is deficient (2,3). In phase 1, APX005M showed dose-dependent activation of APCs in peripheral blood and favorable tolerability. We designed a phase II study evaluating D+A as a novel combination for STS. Methods: This is a single-arm, open-label, Simon 2 stage phase II study with safety lead-in evaluating D+A among 27 patients with STS. Pts have advanced STS (excluding GIST and Kaposi sarcoma) for which doxorubicin is appropriate and any prior lines of therapy, including none. Pts receive D 75 mg/m2 and A 0.3 mg/m2 IV day 1 in 21 day cycles. Doxorubicin is stopped after cycle 8 but APX005M may continue. The primary endpoint is the objective response rate (ORR). The study design has power of 85% to show an improvement in ORR from 10% (inactive) to 30% (active) with α = 0.04. Secondary endpoints include PFS and safety. Pts undergo collection of stool specimens at baseline and cycle 3 to evaluate composition of the gut microbiome including effects on clinical outcomes and modulation of microbiome by treatment. Pts undergo paired tumor biopsies at baseline and cycle 2 which are evaluated with gene expression and multiplex immunohistochemistry to evaluate effects of D+A on iME. The study opened in 1/2019. Clinical trial information: NCT03719430.

Abstract CT004: A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients

Abstract Background: Checkpoint inhibitors such as anti-PD-1 are ineffective as single agents for patients (pts) with PDAC. Preclinical data suggest that chemotherapy with agonistic CD40 antibodies can be combined with anti-PD-1 to trigger effective T cell immunity. We conducted a multi-center, open label clinical trial to evaluate the combination of APX005M with nivo and standard chemotherapy (gem and NP). Herein, we report safety and efficacy from the ongoing study. Methods: Pts with previously untreated PDAC were enrolled in 4 cohorts: Gem/NP/APX005M 0.1 mg/kg (B1), Gem/NP/APX005M 0.3 mg/kg (B2), Gem/NP/Nivo/APX005M 0.1 mg/kg (C1) and Gem/NP/Nivo/APX005M 0.3 mg/kg (C2). Primary objectives were to evaluate safety and determine the recommended Phase II dose (RP2D) of APX005M. Secondary objectives included tumor response and immune pharmacodynamics. Analyses were performed on dose-limiting toxicity (DLT)-evaluable subjects, defined as receiving 1 dose of APX005M and ≥ 2 doses of gem/NP during Cycle 1 and remaining on study through Cycle 2 Day 1. Results: N=30 pts dosed; 24 DLT-evaluable (6 per cohort). Median follow up is 32.2 weeks. N=13 (54%) pts experienced an AE leading to discontinuation, and 10 (42%) pts experienced a treatment-related serious AE. Two DLTs were observed, 1 each in cohorts B2 and C1 (grade 3 and 4 febrile neutropenia, respectively). AE rates were similar across cohorts. Four (17%) subjects died (2 each in Cohorts B1 and C1) due to disease progression (n=2) and AE (n=2, sepsis and septic shock in the setting of neutropenia). Within the DLT-evaluable population, best overall responses included 14 (58%) PR (11 confirmed, 3 unconfirmed), 8 (33%) SD, 1 (4%) PD and 1 (4%) NE. Post-baseline tumor assessments were available for 2 of the 6 DLT-inevaluable pts (best overall responses of SD and confirmed PR). Multiplexed IHC analysis of baseline tumors revealed a low CD8 T cell and high macrophage infiltrate. Analysis of circulating mutant KRAS DNA showed marked and rapid decrease with therapy in some pts. Immune profiling of PBMCs at baseline and on-treatment by CyTOF revealed remodeling of the myeloid compartment in response to treatment, with rapid activation of dendritic cells in most pts. Conclusions: Gem/NP/APX005M ± nivo demonstrated manageable safety profiles and promising antitumor activity in untreated metastatic PDAC pts. APX005M 0.3 mg/kg was selected as the dose for a randomized Phase II study in which the primary endpoint is 1-year overall survival. Clinical trial information: NCT02482168. Citation Format: Mark H. O'Hara, Eileen M. O'Reilly, Mick Rosemarie, Gauri Varadhachary, Zev A. Wainberg, Andrew Ko, George A. Fisher, Osama Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Erica L. Carpenter, Travis Hollmann, Pier Federico Gherardini, Lacey Kitch, Cheryl Selinsky, Theresa LaVallee, Ovid C. Trifan, Ute Dugan, Vanessa M. Hubbard-Lucey, Robert H. Vonderheide. A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT004.

A phase I study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of JNJ-64457107, a CD40 agonistic monoclonal antibody, in patients (pts) with advanced solid tumors.

2527 Background: JNJ-64457107 (JNJ-107) is an agonistic human monoclonal (IgG1) antibody targeting CD40, a novel target for anti-tumor immunotherapy with a central role in adaptive and innate immunity. Methods: JNJ-107 was administered intravenously Q2W in treatment cycles of 28 days. Dose escalation was pursued with (w) and without (wo) pre-infusion steroids for mitigation of infusion related reactions (IRRs). Dose-limiting toxicity (DLT), safety, PK, PD and antitumor activity were evaluated. Results: 95 pts of age 18-80 years (median 59) were enrolled in 7 cohorts (n = 50, 75µg/kg – 2000 µg/kg) w/steroids and 5 cohorts (n = 45, 75 µg/kg – 1200 µg/kg) wo/steroids and received 1-26 (median 3) cycles of JNJ-107. Two DLTs occurred: Grade (G) 3 headache lasting 5 days at 1200 µg/kg w/steroids and G3 ALT/AST + G2 bilirubin increase at 1200 µg/kg wo/steroids. Most frequent adverse events (≥20%) were pyrexia (41%), fatigue (39%), pruritus (39%), headache (26%), chills (26%), nausea (22%) and rash (21%). IRRs were reported in 51% of pts (G1-G2 50%, G3 1%). Most commonly reported IRRs (≥10%) were pruritus (31%), rash (15%), chills (13%) and flushing (12%). Cetirizine and Montelukast premedication during dose escalation wo/steroids significantly reduced IRRs. Preliminary PK of JNJ-107 suggest target mediated drug disposition with rapid decline in serum concentrations (half-life of ~13h at 600 µg/kg and ~ 24h at doses ≥1200 µg/kg). Dose proportional increase in Cmax and AUC(last) was observed at doses ≥1200 µg/kg and more than dose proportional increase was seen at lower doses. PD of JNJ-107 demonstrated dose-independent reduction in peripheral blood B cells recovering in a dose-dependent manner. MCP-1, IP-10, MIP-1a, and MIP-1b cytokines showed high-level responses with cytokine/chemokine secretion kinetics consistent, but not confirmatory, for activation of antigen presenting cells. IFNg, TNF, and IL-8 showed moderate responses reflecting downstream T cell activation. Other tested cytokines were at low levels. A partial response lasting 9.2 months was observed in 1 pt with renal cell cancer. 13 (14%) and 10 (11%) pts showed stable disease lasting ≥3 months and ≥ 6 months, respectively. Conclusions: The CD40 agonist JNJ-107 has a manageable safety profile with favorable PK and PD properties. Future clinical development will require combination with either chemotherapy, or other immunotherapies such as antitumor vaccines or checkpoint inhibitors. Clinical trial information: NCT02829099.

Abstract A128: Tumor endothelial cells say IDO to CD40-stimulating immunotherapy

Abstract CD40, a tumor necrosis factor receptor superfamily member, is a promising immune-boosting target in cancer immunotherapy due to its role in promoting antitumor responses of immune cells. CD40 is also expressed on endothelial cells but the response of the tumor-associated vasculature to CD40-stimulating immunotherapy has not been studied. Herein, we have performed RNA-sequencing analysis of murine tumor endothelial cells (TECs) isolated from B16.F10 melanoma and MB49 bladder cancer treated with agonistic CD40 monoclonal antibody (mAb) or isotype control. Gene set and gene ontology enrichment analyses of the differentially expressed genes revealed that CD40 mAb treatment induces interferon-γ (IFNγ) signaling in the tumor microenvironment associated with up-regulation of immunosuppressive genes in TECs, including the enzyme indoleamine 2, 3-dioxygenase 1 (IDO1). Importantly, IDO1 was preferentially expressed in endothelial cells in the tumor and was positively correlated to infiltration of T-cells in the tumor microenvironment. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Collectively, our data suggest that IDO1 up-regulation in TECs occurs as a response to T-cell activation. Combining CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth and increased survival of B16.F10 tumor-bearing mice, which was associated with increased activation of cytotoxic T-cells. Hereby, we have uncovered a novel immunosuppressive feedback mechanism, in which the tumor vasculature limits the response to cancer immunotherapy by up-regulating IDO1. Citation Format: Anna Dimberg, Alexandros Karampatzakis, Sander Tuit, Mohanraj Ramachandran, Grammatiki Fotaki, Luuk van Hooren, Hua Huang, Roberta Lugano, Kaunisto Aura, Peter Ellmark, Sara M Mangsbo, Joachim L. Schultze, Magnus Essand, Maria Georganaki. Tumor endothelial cells say IDO to CD40-stimulating immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A128.

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

ABSTRACTWe report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.

Abstract 4940: Nonredundant roles for immune checkpoint blockade and agonistic CD40 in mediating T-cell responses in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive cancer that is resistant to most treatments, with a five-year survival rate of ~10%. Immune checkpoint blockade (ICB) has had dramatic effects in many tumor histologies, but is ineffective in PDA. CD40 lies upstream of the immune checkpoints in the T-cell activation pathway, presenting a unique opportunity to intercede with T-cell activation independently of ICB. We hypothesized that administering agonistic CD40 antibody would prime effector T-cell populations, synergizing with ICB to provide therapeutic benefit in PDA. We administered agonistic CD40 monoclonal antibody (clone FGK45, anti-CD40) combined with anti-PD1 and anti-CTLA4 monoclonal antibodies (ICB) to mice bearing subcutaneous PDA tumors established using syngeneic tumor cell lines derived from the KrasG12D+/-;Trp53R172H+/-;Pdx-1 Cre (KPC) genetically engineered mouse model of PDA. While tumor regressions were rare in mice treated with ICB or anti-CD40 alone (1/7 mice in each group), 100% of mice treated with ICB + anti-CD40 experienced tumor regressions (7/7 mice). Cell depletion experiments showed early tumor regressions depended primarily on CD4 T cells, although both CD4 and CD8 T cells were required for long-term remission. 50% of mice (4/8) treated with ICB + anti-CD40 remained tumor-free (median survival 112 days) and 3/4 mice resisted tumor rechallenge, indicative of a long-lived memory T-cell response against PDA. Treatment with ICB + anti-CD40, but neither alone, increased the total intratumoral CD3+ T-cell population 3.8-fold (p<0.01), with increases in both the CD4+ and CD8+ T-cell compartments (6.7-fold and 3.3-fold, respectively, p <0.016). CD40 stimulation, but not ICB, modulated the CD4 compartment in the TME, increasing the proportion of CD43+CD11a+ antigen-specific CD4 T helpers (41 - 43% v. 10%, +/-ICB v. control, p <0.03) and reducing FoxP3+ CD4+ T regulatory cells (Tregs) 2.7 to 3.7-fold (+/- ICB, p < 0.0001). This resulted in an increased ratio of CD8 T effector cells to Tregs (7.5 to 10.7 CD8/Treg, anti-CD40 +/-ICB, p<0.01) specifically after treatment with anti-CD40, regardless of ICB addition. ICB alone increased the proportion of proliferating CD8 T cells in the tumor draining lymph node that were ‘"reinvigorated" Eomes+Tbet-Ki67+ (17-19% +/- CD40 v. 8% control, p <0.01), but was unable to increase the same CD8 T-cell population in the tumor. However, the addition of CD40 to ICB reduced the frequency of PD1+ CD8 T effectors in the tumor (25% v. 52% control, p < 0.05), suggesting a tumor-specific benefit of ICB on the exhausted T-cell compartment. These studies reveal the nonredundant roles that agonistic CD40 and ICB play in generating a robust T-cell response against PDA, and highlight the clinical potential of combining CD40 activation with ICB as a novel therapeutic approach in ICB-resistant tumors. Citation Format: Alexander H. Morrison, Katelyn T. Byrne, Robert H. Vonderheide. Nonredundant roles for immune checkpoint blockade and agonistic CD40 in mediating T-cell responses in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4940.