Antitumor Activity In Solid Tumors Research Articles

IMM2510, an anti-PD-L1/VEGF bispecific antibody fusion protein, in patients with advanced solid tumors: A phase I dose-escalation study.

e14506 Background: IMM2510 is a novel bispecific antibody fusion protein targeting PD-L1 and VEGF. The preclinical study demonstrated that IMM2510 induced significantly stronger anti-tumor activity than either monotherapy or combination of PD-L1 inhibitor and anti-VEGF antibody through blocking the PD-1/PD-L1 pathway and thus activate T cells and reducing VEGF-mediated tumor angiogenesis as well as an enhanced ADCC effect. We previously disclosed the preliminary clinical data of IMM2510, and here we further report safety and efficacy results of IMM2510 in the phase I dose escalation study. Methods: A phase I, multicenter, open-label, dose-escalation study, was designed to evaluate the safety, efficacy, recommended phase II dose (RP2D), and pharmacokinetics (PK) of IMM2510 in patients (pts) with advanced solid tumors. The study was designed with an accelerated titration followed by a standard 3+3 design. IMM2510 (0.007, 0.03, 0.1, 0.3, 1.0, 3.0, 6.0, 10.0, 20.0 mg/kg) was administered intravenously Q2W as monotherapy. Results: As of Dec 21, 2023, 33 pts had received IMM2510 at 9 dose levels (0.007-20.0 mg/kg), the median age was 57 years (range 36-74), the median prior line of therapy was 3 (range 1-13), and 27.3% pts received prior anti PD-1/PD-L1 inhibitor therapies. Treatment-related adverse events (TRAEs) occurred in 32 pts (97.0%). Most TRAEs were grade 1 or 2. The most common TRAEs (≥ 20%) of all grades were infusion related reaction (IRR) (72.7%), platelet count decreased (39.4%), anemia (33.3%) and diarrhea (21.2%). Grade ≥3 TRAEs occurred in 11 pts (33.3%). Grade ≥3 TRAEs (≥5%) were IRR (9.1%), platelet count decreased (6.1%), lymphocyte count decreased (6.1%) and diarrhea (6.1%). TRAEs leading to treatment discontinuation occurred in 3 pts (9.1%) which were IRR, hypersensitivity and pyrexia, respectively. No DLT occurred. In 25 response evaluable pts, 3 pts had confirmed PR: 1 pt with sq-NSCLC (onco-driver gene negative, previous IO treatment failure) at 3 mg/kg with tumor shrinkage 46% and still on the treatment with treatment duration over 20 months; 1 pt with sq-NSCLC at 10 mg/kg with tumor shrinkage about 32% along with treatment duration 9.4 months; 1 pt with thymus adeno-squamous carcinoma (PD-L1 CPS 80) at 20 mg/kg with tumor shrinkage over 53% and still remains on the treatment along with treatment duration 8.1 months. In addition, 7 pts with BOR SD and 4 of them had over 15% decreased tumor burden (1 cervical cancer at 3 mg/kg, 2 non-sq NSCLC at 10 and 20 mg/kg respectively, 1 ovarian cancer at 20 mg/kg). The half-life of IMM2510 in 20.0mg/kg dose group was around 6.8 days. The RP2D was determined to be 20.0 mg/kg. Conclusions: IMM2510 is well tolerated in general and preliminary anti-tumor activity in solid tumors is encouraging. The phase Ib/II is ongoing to enroll patients. Clinical trial information: NCT05972460 .

Abstract CT165: A phase 1/2a, multicenter, open-label, first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1311 (a B7-H3-targeting ADC) in patients with advanced/metastatic solid tumors

Abstract Background: B7 homolog 3 protein (B7-H3, an immune checkpoint molecule) overexpression correlates with disease progression and poor prognosis in various cancers, including lung cancer, esophageal cancer, prostate cancer, and melanoma, is therefore as an ideal candidate for targeted immunotherapy. DB-1311 is an antibody-drug conjugate (ADC) comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor via a maleimide tetrapeptide-based cleavable linker, with a drug-to-antibody ratio of approximately 6. Preclinical studies of DB-1311 demonstrated promising antitumor activity in solid tumors and a tolerable safety profile, warranting further clinical development. Methods: This global, first-in-human, Phase 1/2a study includes dose escalation and expansion parts to assess the safety, tolerability, pharmacokinetics, and antitumor activity of DB-1311 in patients (pts) with pretreated advanced/metastatic solid tumors (NCT05914116). Eligible pts must have tumor that has relapsed or progressed on or after standard systemic treatments, or is intolerable with standard treatment, or for which no standard treatment is available; have ECOG PS ≤1; and evidence adequate organ function. Up to 5 ascending dose levels of DB-1311 will be evaluated with an accelerated titration at first dose followed by a classic “3+3” design to identify the maximum tolerated dose and/or recommended phase 2 dose in pts with solid tumors. Phase 2a part will initiate with a randomization (1:1) cohort for dose optimization in pts with small cell lung cancer with two dose levels identified by the safety monitoring committee based on cumulative data from Phase 1 part. The other five cohorts will enroll pts with non-small cell lung cancer, esophageal squamous cell carcinoma, castration-resistant prostate cancer, melanoma, and other solid tumors at the dose level(s) determined based on cumulative data. DB-1311 will be administrated intravenously as monotherapy until disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. The study plans to enroll approximately 90 pts in Phase 1 and 190 in Phase 2a from locations including but not limited to Australia, United States, China, and Taiwan. To the data cut-off 05 Dec 2023, 11 pts have been enrolled in the study. Citation Format: Ying Cheng, Aaron Lisberg, Charlotte Lemech, Afaf Abed, Arvind Chaudhry, Andrew Schmidt, Xin Lu, Zhongyuan Zhu, Wei Gu, Yang Qiu, Rong Shi, Bin Zhang. A phase 1/2a, multicenter, open-label, first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1311 (a B7-H3-targeting ADC) in patients with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT165.

Abstract CT168: A phase 1/2a, multicenter, open-label, non-randomized first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1310 (a HER3-targeting ADC) in patients with advanced/metastatic solid tumors

Abstract Background: Overexpression of epidermal growth factor receptor 3 (HER3 or ERBB3) has been reported in various cancers, including lung, prostate, head and neck, breast, and ovarian cancers, and is associated with disease progression and poor prognosis. DB-1310 is an antibody-drug conjugate (ADC) comprised of a humanized anti-HER3 IgG1 monoclonal antibody, covalently linked to a proprietary DNA topoisomerase I inhibitor (P1021) via a maleimide tetrapeptide-based cleavable linker, with a high drug-to-antibody ratio (~8). Preclinical studies of DB-1310 demonstrated promising antitumor activity in solid tumors and a tolerable safety profile, warranting further clinical development. Methods: This global, first-in-human, Phase 1/2a study includes dose escalation and expansion parts to assess the safety, tolerability, pharmacokinetics, and antitumor activity of DB-1310 in patients (pts) with pretreated advanced/metastatic solid tumors (NCT05785741). Eligible pts must have progressed on or after standard systemic anticancer treatments have ECOG PS ≤1, and evidence adequate organ function. Phase 1 part will evaluate 5 ascending dose levels of DB-1310 with a standard “3+3” design to identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) in pts with advanced/metastatic solid tumors. Phase 2a part will initiate after MTD and/or RP2D are determined and enroll pts with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutation, NSCLC without EGFR activating mutation, castration-resistant prostate cancer, head and neck squamous cell carcinoma, and HER2-positive (immunohistochemistry [IHC] 3+, or IHC 2+ and in situ hybridization-positive) breast cancer (BC). DB-1310 is administrated intravenously every 3 weeks as monotherapy, or plus trastuzumab in pts with HER2-positive BC only, until discontinuation criteria are met. The study plans to enroll approximately 95 pts in Phase 1 and 192 in Phase 2a from the United States and China. Citation Format: Aaron Lisberg, Shun Lu, Alexander Starodub, Harshad Amin, Julia Rotow, Lin Wu, Alexander Spira, Erika Hamilton, Weidi Shen, Liming Liu, Zhongyuan Zhu, Wei Gu, Yang Qiu, Rong Shi, Shengxue Liu. A phase 1/2a, multicenter, open-label, non-randomized first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1310 (a HER3-targeting ADC) in patients with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT168.

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.

AdvanTIG-105: Phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC).

31 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n=27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP <5% (n=28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

AdvanTIG-105: A phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC).

4028 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 4.6 months (95% CI: 3.9, 7.1). Median PFS was 8.2 months (95% CI: 5.8, not evaluable). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n = 27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP < 5% (n = 28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors

BackgroundQL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies.MethodsIn the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated.ResultsBetween March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively.ConclusionsQL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials.Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Pemigatinib For Previously Treated Central Nervous System Tumors With Activating FGFR Mutations or Translocations: Results From FIGHT-207 (S17.004)

Pemigatinib For Previously Treated Central Nervous System Tumors With Activating FGFR Mutations or Translocations: Results From FIGHT-207 (S17.004)

Abstract CT184: Preliminary dose escalation results of ERAS-601 in combination with cetuximab in FLAGSHP-1: a phase I study of ERAS-601, a potent and selective SHP2 inhibitor, in patients with previously treated advanced or metastatic solid tumors

Abstract Background: SHP2 is an oncogenic tyrosine phosphatase that transduces receptor tyrosine kinase signaling to the RAS/MAPK pathway via its phosphatase-mediated regulation of guanine nucleotide exchange factors. ERAS-601 is a potent, selective, and orally bioavailable allosteric inhibitor of SHP2. In combination with cetuximab, an antibody that targets epidermal growth factor receptor (EGFR), ERAS-601 has demonstrated robust nonclinical activity in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) and RAS/RAF wild-type colorectal cancer (CRC) tumors. Method: FLAGSHP-1 is the first-in-human trial of ERAS-601 administered as monotherapy and in combination with other cancer therapies in patients with advanced or metastatic solid tumors. The primary objectives are to characterize the safety profile, determine the maximum tolerated dose (MTD)/recommended dose (RD), and characterize the pharmacokinetics (PK) profile of ERAS-601 as a monotherapy and in combination with other cancer therapies. Secondary objectives include tolerability and antitumor activity in solid tumors. Presented here are results from the combination dose escalation cohorts in which patients received ERAS-601 twice a day for three weeks followed by a one-week break (BID 3/1) in combination with cetuximab (500mg/m2) administered every 2 weeks (Q2W) on a 28-day cycle. Results: As of October 31, 2022, a total of 15 patients with previously treated advanced or metastatic solid tumors received ERAS-601 BID 3/1 at the following dose levels: 20 mg BID 3/1 (n=4), 40 mg BID 3/1 (n=8), or 60 mg BID 3/1 (n=3) in combination with cetuximab. Combination therapy MTD was determined​ to be 40 mg BID 3/1. ERAS-601 Treatment Related Adverse Events (TRAEs) at or below the MTD were all Grade 1 and 2. TRAEs occurring in ≥20% of patients included diarrhea (27%), AST increase (27%), ALT increase (20%), dermatitis acneiform (20%). Grade ≥3 TRAEs included Grade 4 hypokalaemia, Grade 3 diarrhea, platelet count decreased anemia (each 7%); high grade TRAEs were only observed at 60 mg BID 3/1 (above the MTD). Dose limiting toxicities (DLTs) were only observed at the 60mg BID 3/1 dose levels and included Grade 3 platelet count decreased (n=1) and Grade 4 hypokalemia (n=1). Pharmacokinetics of ERAS-601 and cetuximab in combination were generally comparable to historical monotherapy PK values, suggesting lack of drug-drug interaction. The evaluation of clinical activity is still ongoing. Conclusions: ERAS-601 in combination with cetuximab in patients with previously treated advanced or metastatic solid tumors shows promising preliminary safety and tolerability with reversible and manageable TRAEs. Further evaluation in relevant tumor types are ongoing. Citation Format: Meredith McKean, Ezra Rosen, Minal Barve, Tarek Meniawy, Judy Wang, David S. Hong, Jennifer Yang, Zhengrong Li, Roxana Picard, Les Brail, Daniela Vecchio, Thomas John, Ezra Cohen, Gregory Obara, Aparna Parikh. Preliminary dose escalation results of ERAS-601 in combination with cetuximab in FLAGSHP-1: a phase I study of ERAS-601, a potent and selective SHP2 inhibitor, in patients with previously treated advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT184.

Current Challenges and Potential Strategies for Designing a New Generation of Chimeric Antigen Receptor-T cells with High Anti-tumor Activity in Solid Tumors

Current Challenges and Potential Strategies for Designing a New Generation of Chimeric Antigen Receptor-T cells with High Anti-tumor Activity in Solid Tumors

4-1BB-Based CAR T Cells Effectively Reverse Exhaustion and Enhance the Anti-Tumor Immune Response through Autocrine PD-L1 scFv Antibody.

Exhaustion of chimeric antigen receptor (CAR) T cells is one of the limitations for CAR T efficacy in solid tumors and for tumor recurrence after initial CAR T treatment. Tumor treatment with a combination of programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockage and CD28-based CAR T cells has been intensively studied. However, it remains largely unclear whether autocrine single-chain variable fragments (scFv) PD-L1 antibody can improve 4-1BB-based CAR T cell anti-tumor activity and revert CAR T cell exhaustion. Here, we studied T cells engineered with autocrine PD-L1 scFv and 4-1BB-containing CAR. The antitumor activity and exhaustion of CAR T cells were investigated in vitro and in a xenograft cancer model using NCG mice. CAR T cells with autocrine PD-L1 scFv antibody demonstrate enhanced anti-tumor activity in solid tumors and hematologic malignancies by blocking the PD-1/PD-L1 signaling. Importantly, we found that CAR T exhaustion was largely diminished by autocrine PD-L1 scFv antibody in vivo. As such, 4-1BB CAR T with autocrine PD-L1 scFv antibody combined the power of CAR T cells and the immune checkpoint inhibitor, thereby increasing the anti-tumor immune function and CAR T persistence, providing a cell therapy solution for a better clinical outcome.

Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors: The Past and the Future.

Chimeric antigen receptor (CAR) T-cell therapy is the new standard treatment for various indications in patients with advanced hematologic malignancies. Despite the several preclinical and early phase clinical trials, the overall clinical experience has been disappointing when applying this innovative therapy in solid tumors. The failure of CAR T-cell therapy and its limited antitumor activity in solid tumors have been attributed to several mechanisms, including tumor antigen heterogeneity, the hostile tumor microenvironment and poor trafficking of CAR T cells into tumor sites, and the unacceptable toxicities in some settings, among others. However, remarkable improvements have been made in understanding many of these failure mechanisms for which several emerging novel approaches are being applied to overcome these challenges. In this review, after a brief historic background for immunotherapy in solid tumors, we highlight the recent developments achieved in CAR T-cell designs, summarize completed clinical trials, and discuss current challenges facing CAR T-cell therapy and the suggested strategies to overcome these barriers.

148P AdvanTIG-105: Phase Ib dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor with an anti-programmed cell death protein 1 (PD-1) antibody is a promising combination showing antitumor activity in solid tumors. Phase 1/1b open-label study AdvanTIG-105 assessed safety and preliminary antitumor activity of anti-TIGIT monoclonal antibody (mAb) OCI + anti-PD-1 mAb TIS in pts with advanced unresectable solid tumors (NCT04047862). In dose-escalation, OCI + TIS was well tolerated showing preliminary antitumor activity, establishing the recommended phase 2 dose (RP2D) of OCI 900mg IV every 3 weeks (Q3W) plus TIS 200mg IV Q3W.

126P AdvanTIG-105: Phase Ib dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) in patients (pts) with checkpoint inhibitor (CPI)-experienced advanced non-small cell lung cancer (NSCLC)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor with an anti-programmed cell death protein 1 (PD-1) antibody is a promising combination showing antitumor activity in solid tumors. Phase 1/1b open-label study AdvanTIG-105 assessed safety and preliminary antitumor activity of anti-TIGIT monoclonal antibody (mAb) OCI + anti-PD-1 mAb TIS in pts with advanced solid tumors (NCT04047862). During dose-escalation, OCI + TIS was well tolerated showing antitumor activity, establishing the recommended phase 2 dose (RP2D) of OCI 900mg IV Q3W plus TIS 200mg IV Q3W.

WASH regulates the oxidative stress Nrf2/ARE pathway to inhibit proliferation and promote apoptosis of HeLa cells under the action of Jolkinolide B.

Jolkinolide B (JB), a diterpenoid compound isolated from the roots of Euphorbia fischeriana, has gained research attention for its antitumor effects. In recent years, JB reportedly displayed anti-tumor activity in solid tumors, such as breast, ovarian, and prostate cancer, and leukemia. In this study, we evaluated the effect of JB on HeLa cells with a focus on cell growth inhibition and related mechanisms. HeLa cells were cultured in vitro and divided into a blank control group, HeLa-Scramble (0, 0.25, 0.5 mM), and Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) protein silenced group, HeLa-shWASH (0, 0.25, 0.5 mM). Morphological changes were observed using an inverted microscope. The inhibition rate of cell proliferation was detected using the WST-1 method. Flow cytometry Brdu+PI double standard method was used to detect cell replication ability and FITC+PI double standard method was used to detect cell apoptosis rate. Western blot was used to verify the expression of Nrf2, HO-1, WASH, Bax, Bcl-2, and PCNA. The mRNA expression of cytokines (IL-1α, IL-6, and IL-8) was detected using RT-qPCR. The results showed that JB induced cell apoptosis and arrested cells at the G2/M phase in HeLa-shWASH cells compared with HeLa-Scramble cells (P < 0.05, P < 0.01, respectively). In addition, JB upregulated IL-1α, IL-6, and IL-8 in HeLa-shWASH cells. We conclude that WASH protein participates in JB-induced regulation of the Nrf2/ARE pathway, aggravates inflammatory responses, and promotes cancer cell apoptosis, thus inhibiting the proliferation and invasion abilities of HeLa cells. JB may have anti-tumor effects and potential clinical value for the treatment of cervical cancer.

Synthetic IL9 Receptors Improve Adoptive T-cell Therapies

Chimeric orthogonal IL9 receptor-signaling T cells have superior antitumor activity in solid tumors.

Abstract 584: Driving anti-tumor activity in solid tumors with controlled arming of allogeneic CAR-NK cells

Abstract Recent successes with cell therapies, including CAR-T and CAR-NK cells, for hematopoietic cancers have yet to translate into solid tumors. The major obstacle solid tumors present for cell therapy is the highly immunosuppressive tumor microenvironment (TME), which can impair the function of endogenous as well as therapeutic immune cells. To overcome this challenge, Senti Bio is developing gene circuits to arm CAR-NK cells with multiple cytokines to improve the cytotoxicity and persistence of CAR-NK product candidates. Cytokines, as well as other immune effectors, can act in autocrine or paracrine manner, benefiting the CAR-NK cells as well as potentially engaging the local immune system in the TME. Secreted cytokines can be widely distributed and stimulate other immune cells in the TME, however this is often associated with systemic toxicity as well as reduced impact on the CAR-NK cells. On the other hand, membrane-bound cytokines result in a localized and potent stimulation of the CAR-NK cells but have limited impact on the broader TME. Since IL-15 is known to stimulate NK cell survival and function, Senti Bio has created a novel calibrated release (cr) technology to specifically optimize IL-15 signaling in its CAR-NK platform. crIL-15 is tethered to the NK cells via a cleavable linker that allows for IL-15 release upon cleavage by a ubiquitously expressed protease on the cell surface of NK cells. The rate of linker cleavage can be calibrated by engineering the sensitivity of the cleavable linker sequence to the cell surface protease, thereby enabling the tuning of the ratio of membrane tethered versus fully secreted protein. We compared the function of the wildtype IL-15 protein with different variants of crIL-15 that have a faster or slower release. We demonstrated that crIL-15 has a more potent function, stimulating pSTAT5 signaling and driving expansion and survival of NK cells. CAR-NK cells armed with crIL-15 significantly outperformed CAR-NK cells that expressed the wildtype IL-15 protein, had enhanced function, and demonstrated significantly improved cytotoxicity over three rounds of serial killing (p&amp;lt;0.0001). In parallel, we armed CAR-NK cells with gene circuits that encoded various combinations of two or more cytokines. In particular, the combination of IL-15 and IL-21 resulted in a synergistic effect, leading to longer survival in the absence of cytokines compared to NK cells armed with IL-15 alone. Furthermore, CAR-NK cells armed with IL-15 + IL-21 had significantly increased activity and cytotoxicity compared to CAR-NK cells armed with either cytokine alone (up to 4-times increased cytotoxicity, p&amp;lt;0.0001) when co-cultured with tumor cells. Overall, our results suggest the advantage of multi-arming CAR-NK cells with cytokines, using controlled release systems and cytokine combinations, resulting in improved NK cell function in solid tumor models. Citation Format: Alba Gonzalez, Michelle Hung, Marcela Guzman, Aldo Sotelo, Nicholas Frankel, Yin Yin Chong, Deepika Kaveri, Poornima Ramkumar, Elizabeth Leitner, Priscilla Wong, Ronni Ponek, Kelly Lee, Alyssa L. Mullenix, Russell M. Gordley, Gary Lee. Driving anti-tumor activity in solid tumors with controlled arming of allogeneic CAR-NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 584.

Abstract 596: IOH-001, a novel CD47/PD-L1 bispecific antibody, enhances anti-tumor activity in solid tumors

Abstract Background: The survived cancer cells after cytotoxic chemotherapy are known to promote immune evasion phenotype by increasing the expression of PD-L1 and CD47. Targeting of CD47 and PD-L1 is predicted to overcome immune evasion by coordinately restoring each innate and adaptive immunity. IOH-001, a CD47/PD-L1 dual-targeting bispecific antibody, has been shown to activate immune cells in tumor microenvironment by blocking PD-1/PD-L1 signals that inhibit cytotoxic T-cells, while also blocking interaction with CD47/SIRPa between cancer cells and macrophages. We have investigated whether IOH-001 inhibits tumor growth via co-targeting tumor cells or not. Methods: To assess the function of IOH-001, a series of in vitro functional assays including cell surface binding, antibody-dependent cellular cytotoxicity (ADCC), phagocytosis assays and mixed lymphocyte reaction (MLR) assay were performed compared with the parent antibody. In vivo efficacy of IOH-001 was tested in colon cancer mouse models with human genes KI. Results: IOH-001 has been shown to be bound strongly to various types of PD-L1/CD47-expressing cancer cells including the ones in solid and hematological cancers. In most cancer cells, IOH-001 was demonstrated to have a lower EC50 than the parental antibodies and to be bound in a dose-dependent manner as well. Interestingly, IOH-001 also has shown the selectivity to bind only to cancer cells even under the conditions of co-culturing RBC and cancer cells. IOH-001 has induced phagocytosis of cancer cells by human blood CD14+ monocyte-derived macrophages. Since IOH-001 is an IgG1 type antibody, ADCC and IFN-r expression have been increased compared with the parental antibodies. Consistent with the in vitro data, IOH-001 has more strongly suppressed tumor growth than the combination treatment of the parental antibodies in a dose-dependent manner in syngeneic animal models. Moreover, the tumor of the CR mouse has been identified not to be re-generated in the re-challenge model. Conclusion: IOH-001, dual-blockage of anti-CD47 and anti-PD-L1, has shown the benefits in treating some solid tumors. Bispecific antibody IOH-001 is more likely to work better in targeting tumor cells than the combination of anti-CD47 and anti-PD-L1. Preclinical efficacy results of IOH-001 provide a strong rationale for assessing therapeutic potential in clinical studies. Citation Format: Jeong-kook Kim, A-Ra Jeon, Jihyun Park, Ji Yea Choi, Ji Eun Park, Sun Kwang Song, Ji Hye Choi, Heewook Shin, Ji Hye Lee, Ji Hye Yun, Yoen Hee Ahn, Heung Tae Kim. IOH-001, a novel CD47/PD-L1 bispecific antibody, enhances anti-tumor activity in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 596.

84P SHR-1316 vs placebo in combination with chemotherapy as perioperative treatment in patients with resectable stage II-III NSCLC: A randomized, double-blind, multicenter, phase Ib/III trial

SHR-1316 is a humanized IgG4 monoclonal PD-L1 antibody which has shown promising antitumor activity in solid tumors. This phase 1b/3 trial evaluates the efficacy and safety of SHR-1316 plus chemotherapy vs placebo plus chemotherapy as perioperative treatment for resectable NSCLC. Here, we reported the results from the phase 1b study. Eligible patients were resectable stage II and III (IIIA and T3N2M0 IIIB) NSCLCs without EGFR/ALK alterations. Patients received neoadjuvant treatment with 3 cycles of intravenous SHR-1316 (20 mg/kg on day 1), nab-paclitaxel (100 mg/m2 on days 1, 8, and 15), and carboplatin (area under the curve 5, 5 mg/mL per min on day 1), of each 21-day cycle, followed by surgical resection. After that, patients further received 16 cycles of SHR-1316 (20 mg/kg on day 1) adjuvant treatment. The primary endpoint was major pathological response (MPR) per blinded independent pathological review (BIPR), defined as ≤10% viable tumor cells in resection specimen. If MPR was >55% then phase 3 trial will be initiated. From Jul 14, 2020 to May 12, 2021, 37 patients received SHR-1316 plus chemotherapy neoadjuvant treatment and 34 patients underwent surgery. As of data cutoff on Nov 26, 2021, 19 (55.9%, 95% CI 39.5-71.1) of the 34 patients underwent surgery achieved MPR per BIPR and 11 (32.4%, 95% CI 19.1-49.2) patients achieved pathological complete response. Of the 37 patients received neoadjuvant treatment, 26 (70.3%, 95% CI 54.2-82.5) patients had an objective response per RECIST v1.1, including 1 with complete response and 25 with partial response. Treatment-related adverse events (AEs) were reported in 37 (100%) patients. 29 (78.4%) patients had grade ≥3 treatment-related AEs and 9 (24.3%) had treatment-related serious AEs. No treatment-related deaths occurred. Grade ≥3 surgery-related AEs within 30 or 90 days after surgery were both reported in 6 (17.6%) of the 34 patients. SHR-1316 in combination with nab-paclitaxel and carboplatin as neoadjuvant therapy showed a high proportion of MPR in resectable NSCLC, and the safety profile was well tolerated. Based on the phase 1b results, the phase 3 trial was initiated and ongoing.

Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors

BackgroundThe combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab...