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Investigational immunotherapy

1027TiP - A phase Ib study of CM24 in combination with nivolumab in adults with advanced solid tumors, followed by a phase IIa study of CM24 in combination with nivolumab in NSCLC, and in combination with nivolumab and nab-paclitaxel in pancreatic cancer

Presentation Number
1027TiP
Speakers
  • Erkut Borazanci (Scottsdale, United States of America)

Abstract

Background

The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) has a number of important roles in the cancer phenotype, including angiogenesis, mediation of neutrophil extracellular trap activity, regulation of NK and CD8+ T-cells, the immune exclusion phenotype of therapy resistance, as well as regulation of TIM3. CM24 is an IgG4 which has been found to block CEACAM1 interactions and has been evaluated in an initial phase I trial (Shapira, R. et al., ASCO 2020) as a single agent at 7 dose levels ranging between 0.01mg/kg and 10mg/kg. No dose limiting toxicities were observed in this study and PK analysis suggested that CM24 doses higher than 10mg/kg should be administered q2w to obtain full receptor occupancy.

Trial design

The phase I/II (Clinical trial: NCT04731467) initiated in February 2021 and encompasses a dose escalation of CM24 from 10 to 20mg/kg administered q2w with nivolumab 480mg q4w for the treatment of refractory cancer patients, with the primary objective to evaluate safety, tolerability, PK and determine the recommended phase II dose (RP2D). During the dose escalation phase, patients are enrolled in dose cohorts in a conventional 3+3 design. This part will be followed by 2 expansion cohorts: the first includes patients with NSCLC refractory to first-line immunotherapy, receiving CM24 RP2D q2w in combination with nivolumab; the second includes patients with metastatic pancreatic adenocarcinoma whose disease progressed after first-line treatment, receiving CM24 RP2D q2w in combination with nab-paclitaxel and nivolumab. The primary objective of the expansion parts is ORR. CEACAM1 measurements in serum, biopsy specimens and TILs as well as tumor and TILs PDL1 levels will be evaluated as potential biomarkers. Blockade of CEACAM1 by CM24 in combination with nivolumab or nivolumab and nab-paclitaxel, may provide patients with refractory malignancies with an important treatment option. Preliminary safety and efficacy data from the study will be presented at the conference.

Clinical trial identification

NCT04731467.

Legal entity responsible for the study

Purple Biotech Ltd. (FameWave Ltd.).

Funding

Purple Biotech Ltd. (FameWave Ltd.).

Disclosure

G. Markel: Financial Interests, Personal, Advisory Board, FameWave Ltd. is a fully owned subsidiary of Purple Biotech Ltd.: Purple Biotech. M. Schickler: Financial Interests, Personal, Full or part-time Employment, FameWave Ltd. is a fully owned subsidiary of Purple Biotech Ltd.: Purple Biotech Ltd. H. Reuveni: Financial Interests, Personal, Full or part-time Employment, FameWave Ltd. is a fully owned subsidiary of Purple Biotech Ltd.: Purple Biotech Ltd. L. Jin: Non-Financial Interests, Sponsor/Funding, BMS is a collaborator in the trial: Purple Biotech Ltd. B. Liang: Financial Interests, Personal, Full or part-time Employment, FameWave Ltd. is a fully owned subsidiary of Purple Biotech Ltd.: Purple Biotech Ltd. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

978P - A prospective study of camrelizumab monotherapy following definitive concurrent chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell cancer

Presentation Number
978P
Speakers
  • Jun Wang (Shijiazhuang, China)

Abstract

Background

Definitive concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC). However, ESCC patients (pts) receiving CCRT are still unsatisfactory in terms of local control and overall survival (OS). The PACIFIC study has confirmed that consolidation immunotherapy with durvalumab significantly improves the progression-free survival (PFS) and OS. We conducted a clinical trial to evaluate the safety and efficacy of the camrelizumab (anti-PD-1) following definitive CCRT in pts with unresectable locally advanced ESCC, having hypothesized that consolidation with anti-PD-1 agents after CCRT could enhance the treatment efficacies.

Methods

This is a single-arm exploratory study to determine the safety and feasibility of this approach. camrelizumab was given intravenously over 30 min at a dose of 200 mg on day 1 of each 2-week cycle. Key eligibility criteria included as follows: pts diagnosed with inoperable locally advanced ESCC with 18-75 years old; pts with the clinical stage of Ⅱ-Ⅳa (T1bN+M0, T2-4N0-2M0); had received definitive concurrent chemoradiotherapy (50-60Gy with involved-field irradiation); ECOG performance status is 0-2; pts with measurable lesions (according to the criteria in RECIST1.1); and organ function is in the normal range. The primary end point was PFS.

Results

Eleven pts with ESCC were recruited between April 2020 and March 2021.The median follow-up time of pts was 6.9 months. Of them, 8 of 9 pts with stable disease. 1of 9 with progressive disease. The median PFS was not reached. The mean lung dose (MLD) and V20 of total lung was 1168.2Gy (range:838.2-1389.8Gy) and 23% (range:16-27%), respectively. The most common grade 1 or 2 adverse events included reactive cutaneous capillary endothelial proliferation (6/11), pneumonitis (4/11), hypothyroidism (1/11), hyperthyroidism (1/11), nausea (1/11), transfusion reaction (1/11). one patient had grade 3 transfusion reaction.

Conclusions

Camrelizumab is a well tolerated potential treatment option for ESCC patients who had received definitive concurrent chemoradiotherapy.

Clinical trial identification

NCT04286958.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Investigational immunotherapy

992P - Pan-cancer T-cell priming transcriptomic markers reveals interpatient immunomic heterogeneity independent of histologic type

Presentation Number
992P
Speakers
  • Hirotakka Miyashita (New York, United States of America)

Abstract

Background

Immune checkpoint blockade is effective for only a subset of cancers. Targeting T-cell priming markers (TPM) may enhance activity, but clinical trial data suggest that proper application of these agents is a challenge due to immune complexity and heterogeneity. Herein, we interrogated TPM transcriptomics in a pan-cancer cohort.

Methods

Fifteen TPM markers (CD137, CD27, CD28, CD80, CD86, CD40, CD40LG, GITR, ICOS, ICOSLG, OX40, OX40LG, GZMB, IFNG, and TBX21) were analyzed (N=514 patients). Transcript abundance was normalized to internal housekeeping gene profiles and ranked as a percentile (0-100) by comparing RNA levels to a reference population of 753 tumors spanning 35 histologies. Ranks were categorized by range: “Low” (0-24), “Medium” (25-74), and “High” (75-100). TPM’s rank vs histological type, microsatellite instability high (MSI-H), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) were analyzed (including Bonferroni correction for multiple comparisons).

Results

Among 514 patients (60% female; median age, 61), the most common histological types were colorectal (27%), pancreatic (11%), and breast cancer (10%). Overall, 502 patients (98%) had unique patterns of TPM expression profiles (non-identical to any other patient). No statistically significant association between histological types and TPM expression was seen. In contrast, expression of GZMB and IFNG were significantly higher in tumors with MSI-H, TMB≥10 mutations/mb and PD-L1≥1% by immunohistochemistry (IHC). PD-L1≥1% was also associated with significantly higher expression of CD137, GITR, and ICOS. Patients’ tumors were classified into “Hot”, “Mixed”, or “Cold” clusters (N = 89, 176, and 249, respectively) (Ward’s method). Histological types, MSI status, and TMB were not associated with the clusters, however, the cold cluster showed a significantly lower proportion of tumors with PD-L1 ≥1%. (22% vs 44% in hot and 40% in mixed cluster).

Conclusions

Diverse expression patterns of TPM independent of histological types are described. Individualized selection of patients based on TPM immunomic profiles may be necessary for immunotherapy optimization.

Legal entity responsible for the study

The authors.

Funding

Omniseq.

Disclosure

R. Kurzrock: Financial Interests, Institutional, Sponsor/Funding: Boehringer Ingelheim; Financial Interests, Institutional, Sponsor/Funding: Debiopharm; Financial Interests, Institutional, Sponsor/Funding: Foundation Medicine; Financial Interests, Institutional, Sponsor/Funding: Genentech; Financial Interests, Institutional, Sponsor/Funding: Grifols; Financial Interests, Institutional, Sponsor/Funding: Guardant; Financial Interests, Institutional, Sponsor/Funding: Incyte; Financial Interests, Institutional, Sponsor/Funding: Konica Minolta; Financial Interests, Institutional, Sponsor/Funding: Medimmune; Financial Interests, Institutional, Sponsor/Funding: Merck Serono; Financial Interests, Institutional, Sponsor/Funding: Omniseq; Financial Interests, Institutional, Sponsor/Funding: Pfizer; Financial Interests, Institutional, Sponsor/Funding: Sequenom; Financial Interests, Institutional, Sponsor/Funding: Takeda; Financial Interests, Institutional, Sponsor/Funding: TopAlliance; Financial Interests, Personal, Invited Speaker: Actuate Therapeutics; Financial Interests, Personal, Invited Speaker: Bicara Therapeutics, Inc.; Financial Interests, Personal, Invited Speaker: Biological Dynamics; Financial Interests, Personal, Invited Speaker: Neomed; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: TD2/Volastra; Financial Interests, Personal, Invited Speaker: Turning Point Therapeutics; Financial Interests, Personal, Invited Speaker: X-Biotech; Financial Interests, Personal, Stocks/Shares: CureMatch Inc.; Financial Interests, Personal, Stocks/Shares: IDbyDNA; Financial Interests, Personal, Member of the Board of Directors: CureMatch; Financial Interests, Personal, Member of the Board of Directors: CureMetrix; Financial Interests, Personal, Ownership Interest: CureMatch . N. Bevins: Financial Interests, Personal, Invited Speaker: Thermo Fisher. S. Pabla: Financial Interests, Personal, Stocks/Shares: Omniseq. M. Nesline: Financial Interests, Personal, Stocks/Shares: Omniseq. S. Glenn: Financial Interests, Personal, Stocks/Shares: Omniseq. J. Conroy: Financial Interests, Personal, Stocks/Shares: Omniseq. P. DePietro: Financial Interests, Personal, Stocks/Shares: Omniseq. S. Kato: Financial Interests, Personal, Advisory Board: Foundation Medicine; Financial Interests, Personal, Advisory Board: NeoGenomics; Financial Interests, Personal, Advisory Board: CureMatch; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal and Institutional, Sponsor/Funding: ACT Genomics; Financial Interests, Personal and Institutional, Sponsor/Funding: Sysmex; Financial Interests, Personal and Institutional, Sponsor/Funding: Konica Minolta; Financial Interests, Personal and Institutional, Sponsor/Funding: OmniSeq. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

1032TiP - A phase I, first-in-human, study of TILT-123, a tumor-selective oncolytic adenovirus encoding TNFa and IL-2, in participants with advanced melanoma receiving adoptive T-cell therapy with tumor-infiltrating lymphocytes

Presentation Number
1032TiP
Speakers
  • Inge-Marie Svane (Herlev, Denmark)

Abstract

Background

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TIL) has demonstrated that potent and long-lasting antitumor responses can be achieved with cellular cancer immunotherapy in solid tumor patients. Yet, the therapy yields various toxicities, due to toxic lymphodepleting preconditioning and IL-2 postconditioning. With the intent of decreasing conditioning-related toxicities, while retaining efficacy, we developed TILT-123 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2), a novel oncolytic adenovirus designed to reinvigorate antitumor T-cells. Preclinical data indicates that TILT-123 modulates the tumor milieu, leading to increased activity and trafficking of antitumor T-cells. TILT-123 enhances the efficacy of adoptive T-cell therapy, without conditioning regimens, curing 100% of tumor-bearing test animals and inducing tumor-specific immunological memory. This warrants clinical investigation.

Trial design

An open-label, dose-escalation, phase I clinical trial (NCT04217473) is assessing the safety of the approach in refractory or recurrent stage III/IV melanoma patients, which cannot be treated with curative intent with available therapies and are eligible for TIL therapy. Patients receive TILT-123 intravenously and intratumorally, and TIL therapy without pre- or postconditioning. Patients must have at least one biopsiable/operable tumor for TIL generation and another injectable lesion for intratumoral TILT-123 administration. The primary endpoint of the trial is safety of TILT-123 by day 36 (prior to TIL administration), based on the incidence of serious and non-serious adverse events, vital signs, ECG, and safety laboratory results. Secondary endpoints include evaluation of safety and tolerability for the duration of the trial, antitumor efficacy, antitumor responses, and biological effects against tumors. Enrollment began in 2020 and, at the time of submission, cohort 1 was completed without DLTs, and cohort 2 enrolment is in progress. Interim safety, efficacy, biological, immunological, and biosafety data will be presented.

Clinical trial identification

NCT04217473.

Legal entity responsible for the study

TILT Biotherapeutics Ltd.

Funding

TILT Biotherapeutics Ltd.

Disclosure

I. Svane: Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Writing Engagements: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Cofounder and Founder Warrents: IO Biotech; Financial Interests, Personal, Stocks/Shares: IO Biotech; Non-Financial Interests, Institutional, Research Grant: Adaptimmune; Non-Financial Interests, Institutional, Research Grant: Enara Bio; Non-Financial Interests, Institutional, Funding: Evaxion; Non-Financial Interests, Institutional, Research Grant: Lytix Biopharma; Non-Financial Interests, Institutional, Research Grant: TILT Biotherapeutics; Non-Financial Interests, Principal Investigator: BMS; Non-Financial Interests, Principal Investigator: Lytix Biopharma; Non-Financial Interests, Principal Investigator: Novartis; Non-Financial Interests, Principal Investigator: Roche; Non-Financial Interests, Principal Investigator: TILT Biotherapeutics. J.M. Santos: Financial Interests, Institutional, Full or part-time Employment: TILT Biotherapeutics Ltd; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd. V. Cervera-Carrascon: Financial Interests, Institutional, Full or part-time Employment: TILT Biotherapeutics Ltd; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd. R. Havunen: Financial Interests, Institutional, Full or part-time Employment: TILT Biotherapeutics Ltd. S. Sorsa: Financial Interests, Institutional, Full or part-time Employment: TILT Biotherapeutics Ltd. E. Ellebæk: Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Kyowa Kirin; Financial Interests, Personal, Other, Travel/conference expenses: MSD. T. Monberg: Non-Financial Interests, Other, Study site coordinator in clinical trial: BMS; Non-Financial Interests, Other, Study site coordinator in clinical trial: Lytix Biopharma. M. Donia: Financial Interests, Personal, Invited Speaker, Teaching: Novartis; Financial Interests, Personal, Invited Speaker, Teaching: Roche; Non-Financial Interests, Other, Sub-investigator of clinical trial with connected translational research: Bristol Myers Squibb. A. Hemminki: Financial Interests, Institutional, Full or part-time Employment, Chief Executive Officer: TILT Biotherapeutics Ltd; Financial Interests, Personal, Other, Founder: TILT Biotherapeutics Ltd; Financial Interests, Institutional, Member of the Board of Directors: TILT Biotherapeutics Ltd; Financial Interests, Personal, Stocks/Shares: Targovax ASA; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

1017P - Preclinical evaluation of KD033, a human anti-PD-L1/IL-15 bispecific protein, in human PD-1/PD-L1 transgenic C57/Bl6 mice with PD-L1 positive and negative tumors

Presentation Number
1017P
Speakers
  • Stella Martomo (New York, United States of America)

Abstract

Background

KD033 is a clinical-stage bispecific fusion molecule consisting of a high-affinity anti-human-PD-L1 antibody and human IL-15. Previous preclinical studies with mouse anti-PD-L1/IL-15 (KD033 surrogate) have demonstrated that targeting IL-15 with anti-PD-L1 antibody resulted in increased efficacy, safety and maximal tolerated dose of the fusion protein compared to administrations of free IL-15. Reduction of tumor growth in both PD-L1 positive and negative tumor models was also observed. (Mol Cancer Ther, February 1 2021 (20) (2) 347-356) The goal of the current study is to evaluate the efficacy of KD033, the human anti-PD-L1/IL-15, in a human PD-1/PD-L1 transgenic mice, with human-PD-L1 positive and negative tumor cells.

Methods

KD033 was administered in the human-PD-L1/PD-1 transgenic C57/Bl6 mice subcutaneously transplanted with human(h)-PD-L1 positive and negative MC38 colon carcinoma cells. This animal model allowed the evaluation of human anti- PD-1 or PD-L1 agents. Furthermore, this model can be used to evaluate the efficacy of anti-PD-L1- targeting agents when PD-L1 is expressed in the animal but is either absent or present on the tumor cells.

Results

As was observed with KD033 surrogate, KD033 treatment resulted in significant tumor growth reduction in both h-PD-L1 positive and negative MC38 tumors. Analysis of peripheral immune cell populations showed similar increases in CD8 T and NK cells between h-PD-L1 positive and negative MC38- bearing mice after KD033 administration. Immunohistochemistry demonstrated an increase in CD8 T-cell infiltration into the h-PD-L1 positive MC38 tumors, whereas NK cells infiltration was more pronounced in the h-PD-L1 negative MC38 tumors. Analysis of tumor gene transcription after KD033 treatment highlighted differences in gene signatures between h-PD-L1 positive and negative MC38 tumors following KD033 treatment.

Conclusions

These results showed that the efficacy of anti-PD-L1-IL-15 fusion protein is not limited to PD-L1 tumor expression as KD033 was efficacious in both PD-L1 positive and negative tumors.

Legal entity responsible for the study

The study was done by Kadmon Corporation, LLC. Animal studies were conducted in WuxiAppTec Inc. with approved SOP and IACUC protocol. Nanostring platform analysis was done for Kadmon by Canopy Biosciences.

Funding

Kadmon Corporation, LLC.

Disclosure

S. Martomo: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. D. Lu: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. Z. Polonskaya: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. X. Luna: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. Z. Zhang: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. G. Regev: Financial Interests, Personal, Full or part-time Employment: Kadmon Pharmaceutical; Financial Interests, Personal, Stocks/Shares: Kadmon Pharmaceutical. O. Schueller: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation. J. Patel: Financial Interests, Personal, Full or part-time Employment: Kadmon Corporation; Financial Interests, Personal, Stocks/Shares: Kadmon Corporation.

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Investigational immunotherapy

1015P - A phase I dose-escalation study of HBM4003: An anti-CTLA-4 heavy-chain-only mAb

Presentation Number
1015P
Speakers
  • Paul De Souza (Campbelltown, Australia)

Abstract

Background

HBM4003 is a fully heavy-chain-only monoclonal antibody (mAb) to CTLA-4, which was engineered to deplete Treg cells by enhanced ADCC.

Methods

This is a first-in-human, phase I study to evaluate the safety, anti-tumor activity, PK/PD and recommended phase II dose of HBM4003. In part 1 (presented here), patients (pts) were enrolled into 3 dose levels (DL): 0.3mg/kg QW (28-day cycle), 0.45mg/kg Q3W (21-day cycle), and 0.6mg/kg Q3W (21-day cycle). Part 2 is a dose-expansion study.

Results

The study is ongoing. Twenty pts with advanced solid tumors have been treated at 4 Australian sites; 13 pts received ≥ 2 lines of systemic therapies and 8 received previous PD-1/PD-L1 mAb. The most common treatment-related AE (TRAE) of all grades was diarrhea (8[40%] pts), followed by colitis (5[25%] pts). Grade (Gr) 3 TRAEs are shown in the table.

Grade (Gr) 3 TRAEs

DL N, Enrolled (n, evaluable) Gr 3 TRAE n, % Gr 3 Diarrhea * n, %
0.3mg/kg QW 7 (6) diarrhea, 2, 28.6% diarrhea, 2, 28.6%
0.45mg/kg Q3W 7 (6) increased blood bilirubin and LFT increased**,1, 14.3% 0
0.6mg/kg Q3W 6 (6) diarrhea, 4, 66.7% diarrhea, 4, 66.7%

*No associated colitis or typical pathological changes, resolved with standard steroid treatment **Total bilirubin increased from normal to Gr 3, and LFT increased from Gr 1 to Gr 3. Other TRAEs included pruritus (3 [15%] pts), rash (4 [20%] pts), and hyperhidrosis (1 [5%] pt); all were Gr 1 or 2. There was 1 DLT (0.3mg/kg QW) with Gr 2 colitis and Gr 3 diarrhea. TRAE leading to discontinuation occurred in 8 pts. No DLT was observed in the Q3W DL. No Gr 4 or Gr 5 TRAE was reported. Fourteen pts were evaluable for efficacy: 9 had SD as best response, whereas 1 pt had confirmed PR as best response [0.45mg/kg Q3W, HCC, pre-treated with sorafenib, lenvatinib, and anti-PD-1, with tumor shrinkage of 22.2% (Week 6), 48.9% (Week 12), 53.3% (Week 16), and 64.4% (Week 24); AFP also declined from 170 u/l to <10u/l at Week 24], and 1pt (0.3mg/kg QW, CRPC) had SD with a PSA response. HBM4003 demonstrated near dose-proportional PK and extended PD effect. Immunogenicity was low.

Conclusions

Preliminary results for HBM4003 are encouraging. At 0.45mg/kg Q3W, there was no DLT and no cases of grade 3 diarrhea. There was one confirmed PR. Hence 0.45mg/kg Q3W was selected as the RP2D for part 2.

Clinical trial identification

NCT04135261.

Legal entity responsible for the study

Harbour BioMed US, Inc.

Funding

Harbour BioMed US, Inc.

Disclosure

J. Ji: Financial Interests, Institutional, Full or part-time Employment: HBM Holdings Limited. M.M. de Assis: Financial Interests, Institutional, Full or part-time Employment: HBM Holdings Limited. X. Chen: Financial Interests, Institutional, Full or part-time Employment: HBM Holdings Limited. X. Gan: Financial Interests, Institutional, Full or part-time Employment: HBM Holdings Limited. X. Tao: Financial Interests, Institutional, Full or part-time Employment: HBM Holdings Limited. R. Zuo: Financial Interests, Institutional, Full or part-time Employment: HBM Holdings Limited. G. Ross: Financial Interests, Personal, Full or part-time Employment, Director: Graham Ross Oncology Consulting Services Ltd; Financial Interests, Personal, Stocks/Shares, Former Employee: Roche; Financial Interests, Personal, Stocks/Shares, Wife - Spouse: Roche; Financial Interests, Personal, Stocks/Shares, Former Employee: AstraZeneca; Financial Interests, Institutional, Other, Consultant: HBM Holdings Limited. L. Lu: Financial Interests, Institutional, Full or part-time Employment: HBM Holdings Limited. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

1020P - MPT-0118 a clinical drug candidate to assess Treg reprogramming via MALT1 blockade

Presentation Number
1020P
Speakers
  • Peter Keller (Rockport, United States of America)

Abstract

Background

Despite transforming effects of immune checkpoint therapy (ICT), objective response rates are low in solid tumors. In the tumor microenvironment (TME), regulatory T-cells (Treg) are unstable, likely due to changes in Treg metabolism in the tumor milieu. Destabilized Treg can be reprogrammed to lose their immunosuppressive function and secrete IFN-γ, offering a strategy to sensitize unresponsive tumors to ICT. Blockade of MALT1 protease induces Treg reprogramming in the TME without affecting Treg in healthy tissue. MPT-0118, an orally-dosed MALT1 inhibitor, was developed to reprogram Treg and is currently assessed in patients with advanced tumors.

Methods

Test articles were MPT-0118 and anti-PD-1. In vivo studies in mice assessed anti-tumor effects using D4M.3A, B16F10, and MC38 syngeneic tumors. Studies in rats and dogs assessed pharmacokinetics and safety. Tumor tissues were evaluated for Treg reprogramming by histological imaging and flow cytometry. Murine- and patient-derived organotypic tumor spheroids (MDOTS and PDOTS) were used to determine immune-mediated cell killing ex vivo.

Results

MPT-0118 demonstrated dose-dependent in vivo anti-tumor activity. Consistent with the hypothesis that Treg reprogramming supports anti-tumor immunity by initiating IFN-γ-driven tumor inflammation, the effect was strongest in combination with anti-PD-1 and in models that are not responsive to ICT alone. MPT-0118-treated tumors showed an increase in IFN-γ-secreting Treg, associated with decelerated tumor growth. Ex vivo, MPT-0118 reduced cell viability in D4M.3A MDOTS and colorectal cancer PDOTS in a dose-dependent manner at concentrations also achieved in tumors following in vivo dosing. While MPT-0118 induced Treg reprogramming in tumors, no changes in the frequencies of Treg circulating in blood were detected in rats. Modeling of the human effective dose and toxicology studies demonstrate a >2x therapeutic window in patients.

Conclusions

MPT-0118 Treg reprogramming represents a novel strategy with the potential to mitigate the critical problem of low ICT response rates in solid tumors. MPT-0118 recently started a phase 1/1b dose-escalation and cohort-expansion clinical trial.

Clinical trial identification

NCT04859777.

Legal entity responsible for the study

Monopteros Therapeutics Inc.

Funding

Monopteros Therapeutics Inc.

Disclosure

P. Keller: Financial Interests, Personal, Full or part-time Employment: Monopteros Therapeutics; Non-Financial Interests, Personal, Leadership Role: Divide and Conquer. I. Mazo: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. Y. Gao: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. V. Reddy: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. F. Caballero: Financial Interests, Advisory Role: Monopteros Therapeutics. B. Stephens: Financial Interests, Institutional, Research Grant: Monopteros Therapeutics. R.W. Jenkins: Financial Interests, Personal, Stocks/Shares: Xsphera Bio; Financial Interests, Institutional, Research Grant: Monopteros Therapeutics. U.H. von Andrian: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. T.R. Mempel: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

1012P - Intratumoral immunotherapy with a novel TLR1/2/3 agonist, L-pampo, induces robust anti-tumor immune responses and enhances immune checkpoint blockade

Presentation Number
1012P
Speakers
  • WON SUK LEE (Seongnam, Korea, Republic of)

Abstract

Background

Immunotherapy holds the potential to induce potent and durable responses, but few patients respond favorably. Among numerous strategies to enhance the therapeutic efficacy of cancer immunotherapy, Toll-like receptor (TLR) agonist-based approaches have been studied for a long time since they trigger the innate immunity and generate antigen-specific T-cell responses to fight against cancer. Here, we developed a novel TLR1/2/3 agonist, L-pampoTM, that promotes anti-tumor immunity and enhances immune checkpoint blockade.

Methods

Tumor-bearing mice were intratumorally treated with either L-pampo and/or anti-PD-1 twice a week, and their tumors were measured. The tumors and lymphoid organs were analyzed using flow cytometry, histological, and Nanostring methods.

Results

A potent TLR agonist, L-pampo, was generated by combining a TLR1/2 agonist, Pam3CSK4, and a TLR3 agonist, Poly(I:C). Intratumoral injections of L-pampo suppressed tumor growth in various syngeneic tumor models, namely, MC38 colon cancer, MB49 bladder cancer, and KPC pancreatic cancer. L-pampo promoted CD8+ T-cell infiltration into the tumor, while reducing CD4+ CD25+ FoxP3+ regulatory T-cells. L-pampo also induced robust interferon-gamma secretion from activated T-cells. In bilateral tumor models, intratu moral L-pampo treatment suppressed not only injected tumors but also non-injected tumors, suggesting the activation of systemic immunity by local immunotherapy. L-pampo combined with anti-PD-1 antibody overcame the resistance to PD-1 blockade in non-inflammatory tumors by producing a favorable tumor immune microenvironment.

Conclusions

Overall, our study demonstrated that intratumoral immunotherapy with L-pampo elicits strong anti-tumor immunity within the tumor microenvironment and strengthens the efficacy of immune checkpoint blockade.

Legal entity responsible for the study

C. Kim, H.J. Chon.

Funding

CHA Vaccine Institute.

Disclosure

Y.K. Heo: Other, Institutional, Funding: CHA Vaccine. B.C. Ahn: Other, Institutional, Funding: CHA Vaccine. H.G. Kang: Other, Institutional, Funding: CHA Vaccine. J.K. Cho: Other, Institutional, Funding: CHA Vaccine. J.S. Yum: Other, Institutional, Funding: CHA Vaccine. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

994P - PCR-based analysis of PD-L1 RNA expression in lung cancer: Comparison with commonly utilized immunohistochemical assays

Presentation Number
994P
Speakers
  • Evgeny N. Imyanitov (Saint-Petersburg, Russian Federation)

Abstract

Background

PD-L1 testing is currently performed by immunohistochemical (IHC) analysis of PD-L1-positive cells. We questioned whether the results of PCR-based measurement of PD-L1 RNA expression correlate with IHC scores obtained by different commercial assays.

Methods

167 consecutive non-squamous non-small cell lung carcinomas (NSCLCs) were analyzed for PD-L1 RNA expression and subjected to 22C3, SP263 and SP142 IHC scoring using recommended cut-offs.

Results

RNA and protein expression measurements demonstrated good correlation as continuous variables, however there were discrepancies relative to standard thresholds. PCR-based assay had excellent negative predictive value towards the cut-off of 1% stained tumor cells, given that absent/low RNA expression was observed in 51/52 (98%) and 48/52 (92%) NSCLCs negative by 22C3 and SP263 IHC staining, respectively. Moderate/high PD-L1 RNA expression was registered in 115/167 (69%) cases, while only 64 (56%) of these 115 NSCLCs had expression in more than 1% tumor cells. Among the remaining 51 tumors, 17 (33%) NSCLCs expressed PD-L1 in >/=1% immune cells, 26 (51%) showed PD-L1 staining in 0.1-0.9% tumors cells and 8 (16%) cases were entirely negative by IHC. Similarly, PCR assays showed excellent capability to reveal tumors with <50% stained tumor cells (22C3: 133/139 (96%); SP263: 131/139 (94%)) or with <50% stained tumor cells and <10% stained immune cells (SP142: 137/139 (99%)), however provided insufficient specificity in identifying tumors with IHC PD-L1 expression above these clinically accepted thresholds. 22C3 and SP263 antibodies, which are believed to be interchangeable, showed concordant results for 145/167 (87%) and 162/167 (97%) tumors for 1% and 50% cut-offs, respectively.

Conclusions

Some NSCLCs demonstrate readily detectable PD-L1 expression on the level of RNA, but fall below commonly accepted cut-offs by IHC. It remains to be studied whether these discrepancies are attributed to technical or biological reasons. Clinical sensitivity of these tumors to immune therapy deserves additional investigations.

Legal entity responsible for the study

The authors.

Funding

This study has been supported by the Russian Science Foundation (grant 20-15-00244).

Disclosure

All authors have declared no conflicts of interest.

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Investigational immunotherapy

977P - Interim results of phase I dose escalation study of YBL-006: A novel anti-PD-1 monoclonal antibody in advanced solid tumors

Presentation Number
977P
Speakers
  • Keun-Wook Lee (Seongnam, Korea, Republic of)

Abstract

Background

YBL-006 is a fully human anti-programmed death-1 (PD-1) antibody with a wider binding interface of the PD-1/YBL-006 complex and higher affinity compared to that of other PD-1 antibodies, which showed a favorable safety profile and a potent anti-tumor efficacy in animal models.

Methods

A modified “3+3” design, with the first patient dosed at 0.5 mg/kg (mpk), was followed by conventional dose escalation of 2, 5, and 10 mpk IV. Dose escalation cohort explored the safety, pharmacokinetics (PK), PD-1 receptor occupancy (RO), serum IFN-γ level and tumor response. Adverse events (AEs) were graded using the CTCAE v5. Tumor response was assessed using the RECIST v1.1 every 8 weeks. Exploratory biomarker analysis included whole exome sequencing to assess tumor mutational burden (TMB) and Lunit SCOPE IO to assess the density of intra-tumoral tumor-infiltrating lymphocyte (TIL). The cut-off date for analysis was Apr 27th, 2021.

Results

Total of 11 patients with advanced solid tumors were enrolled in the escalation cohort. YBL-006 showed a linear PK prolife in terms of Cmax and area under the curve by dose escalation and approximately 8 days of T1/2. Both PD-1 RO and serum IFN-γ increased by > 2 times 8 h after the first dose. No dose limiting toxicity (DLTs) or deaths related to YBL-006 have been reported. The most common AEs of Grade 2 ≥ related to YBL-006 were rash (21.7%), fatigue (13%), fever (13%) and hypothyroidism (4.3%). Ten patients were available for tumor response evaluation and their best overall responses included 1 complete response (penile squamous cell carcinoma, 2 mpk), 1 partial response (anal squamous cell carcinoma, 2 mpk) with durable responses lasting more than 30+ and 14+ weeks respectively, and 4 stable disease. Tumor samples of both of 2 responders harbored high levels of TMB (8.3 and 9.3 per megabase) and intra-tumoral TIL density (66.1% and 95.8%).

Conclusions

YBL-006 is well tolerated, and AEs are manageable with the results of no DLTs occurred and the maximum tolerated dose was not reached until progressing to the 10 mpk. Dose expansion cohort using flat dosing is planned.

Clinical trial identification

NCT04450901.

Legal entity responsible for the study

Y-Biologics Inc.

Funding

Y-Biologics Inc.

Disclosure

M. Kim: Financial Interests, Personal, Full or part-time Employment: Y-Biologics; Financial Interests, Personal, Stocks/Shares: Y-Biologics. J. Yoon: Financial Interests, Personal, Full or part-time Employment: Y-Biologics; Financial Interests, Personal, Stocks/Shares: Y-Biologics; Non-Financial Interests, Project Lead: Y-Biologics. H. Lee: Financial Interests, Personal, Full or part-time Employment: Y-Biologics; Financial Interests, Personal, Stocks/Shares: Y-Biologics; Financial Interests, Personal, Leadership Role: Y-Biologics. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

Investigational immunotherapy

Investigational immunotherapy

1024P - Baseline biomarkers associated with clinical benefit in patients with solid tumors refractory to immune checkpoint inhibitors (ICIs) treated with live biotherapeutic MRx0518 in combination with pembrolizumab

Presentation Number
1024P
Speakers
  • Edwin R. Parra (Houston, United States of America)

Abstract

Background

MRx0518 is a novel, gut microbiome derived, single strain oral Live Biotherapeutic Product (LBP) with potent anti-tumour efficacy in multiple cancer models. MRx0518 has been shown to induce activation of CD8+ T-cells and suppress differentiation of Treg cells in vitro, and to increase the CD8/Treg cell ratio in murine models of cancer. In an ongoing phase I/II study (NCT03637803), preliminary antitumor activity has been observed in patient’s refractory to ICIs when MRx0518 is administered in combination with pembrolizumab. This clinical data has been previously reported, and here we present data from biomarker analysis indicating characteristics of patients that have responded.

Methods

Patients received MRx0518 1 capsule PO BID (1x1010 to 1x1011 CFU) and pembrolizumab (200mg Q3W) for up to 2 years or until progression. Eligible patients have experienced clinical benefit from a prior ICI before eventually progressing. Tumour response was assessed every 9 weeks by RECIST v1.1. Responders were classed as patients who experienced CR, PR or SD ≥6 months. To date, baseline FFPE tumour biopsies from 12 patients, 4 responders and 8 non responders, were immunoprofilling using a mIF panel against; CD3, CD8, PD-1, FOXP3, Ki-67, PD-L1, CD68, and cytokeratin antibodies in tumor and stroma compatments form the tissue using image analysis.

Results

Response to therapy was associated with higher baseline densities of tumour infiltrating Treg (CD3+Foxp3+) (P=0.0381) and proliferating total T-cells (CD3+Ki67+) (P=0.0048) at baseline, whereas higher densities of macrophages (CD68+ cells, P=0.0303) were detected in the stroma and tumour tissue compartment of non-responders.

Conclusions

Understanding mechanisms of resistance to ICIs is key in identifying patients who may respond to subsequent therapies. This limited analysis, together with the observations of increased CD8+ T-cell activation and reduced induction of Treg cells in the presence of tolerogenic cytokines in vitro and in preclinical models, provides insight for further investigation into the potential for MRx0518 + pembrolizumab to overcome Treg-mediated acquired resistance to ICIs.

Clinical trial identification

NCT03637803.

Legal entity responsible for the study

4D Pharma PLC.

Funding

4D Pharma PLC.

Disclosure

M. Adriani: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. R. Parikh: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. A. Stevenson: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. C. Badham: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. G. Fyvie: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. M. Chisamore: Other, Institutional, Full or part-time Employment: 7Merck & Co., Inc. All other authors have declared no conflicts of interest.

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