P2, N=24, Recruiting, Ever Supreme Bio Technology Co., Ltd. | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2022 --> Dec 2026

P2/3, N=26, Completed, AlloVir | Active, not recruiting --> Completed

P1/2, N=134, Terminated, Atara Biotherapeutics | Trial completion date: Sep 2027 --> Jan 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2023 --> Nov 2023; Study was terminated as primary endpoint was not achieved

P2/3, N=378, Terminated, AlloVir | Trial completion date: Dec 2024 --> Jan 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Jan 2024; Study discontinued as DSMB determined it was futile. No safety concerns were noted.

P3, N=97, Terminated, AlloVir | Trial completion date: Jun 2024 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Jan 2024; Study discontinued as DSMB determined it was futile. No safety concerns were noted.

P3, N=51, Terminated, AlloVir | N=80 --> 51 | Trial completion date: Jun 2024 --> Jan 2024 | Recruiting --> Terminated; Study discontinued as DSMB determined it was futile. No safety concerns were noted.

P2/3, N=378, Active, not recruiting, AlloVir | Recruiting --> Active, not recruiting

The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that could potentially be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in employing similar novel approaches of antibody-coupled T-cell activation.

P2, N=29, Terminated, Instil Bio | N=130 --> 29 | Trial completion date: Aug 2028 --> Feb 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2024 --> Feb 2023; Business Decision

P1, N=0, Withdrawn, Instil Bio | N=27 --> 0 | Trial completion date: Aug 2028 --> Dec 2022 | Active, not recruiting --> Withdrawn | Trial primary completion date: Feb 2024 --> Dec 2022

Case Background: In June 2022, a 69-year-old woman with relapsed/refractory MM (diagnosed in 2018) received LD chemotherapy containing fludarabine and cyclophosphamide given on Days 1 to 3 before a 2nd round of CAR-T therapy (her first dose was in April 2022)...Urine labs were consistent with acute kidney injury from acute tubular necrosis associated with her severe diarrhea and drug toxicity from cidofovir... The multivirus-specific T cell therapy posoleucel appeared to be safe and effective against refractory disseminated AdV infection in this elderly patient with immune insufficiency as the result of LD chemotherapy and CAR-T.

P1/2, N=9, Suspended, NexImmune Inc. | Trial completion date: Nov 2022 --> Dec 2023 | Terminated --> Suspended | Trial primary completion date: Aug 2022 --> Nov 2023

P1, N=25, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1/2, N=9, Terminated, NexImmune Inc. | N=22 --> 9 | Recruiting --> Terminated; Lack of accrual

P2, N=130, Active, not recruiting, Instil Bio | Recruiting --> Active, not recruiting

P1, N=27, Active, not recruiting, Instil Bio | Recruiting --> Active, not recruiting

P2, N=130, Recruiting, Instil Bio | Trial completion date: Dec 2027 --> Aug 2028 | Trial primary completion date: Jun 2023 --> Mar 2024

P1, N=27, Recruiting, Instil Bio | Not yet recruiting --> Recruiting

P1, N=27, Not yet recruiting, Instil Bio

EBV+LMS is a rare neoplasm which can lead to significant morbidity and mortality in SOT recipients. There is currently no standard approach to therapy. multivirus specific T-cell therapy, such as posoleucuel, offers a targeted approach to consider for EBV-driven malignancies in SOT recipients.

P2, N=24, Recruiting, Ever Supreme Bio Technology Co., Ltd. | Trial completion date: Jun 2022 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2022

Bridging anti-MM treatment was permitted during the manufacture of the cellular product with a wash-out period of at least 14 days prior to lymphodepletion (LD) chemotherapy (intravenous fludarabine 30 mg/m 2 and cyclophosphamide 300 mg/m 2 ), which was administered on Days -5, -4, and -3 prior to the infusion of the NEXI-002 product up to 72 hours later (Day1). RNA Seq transcriptional profiling of the CD8+ T cells is planned. Additional patients have recently received NEXI-002 infusions and the trial will continue to be expanded to gain additional safety, immunologic, and clinical activity experience.

P1, N=26, Terminated, Cogent Biosciences, Inc. | Active, not recruiting --> Terminated; Business decision

P2, N=130, Recruiting, Instil Bio

Results Three patients were treated with single infusions of 80 to 100 million cells of NEXI-002 following lymphodepleting chemotherapy (fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 on Days -5 to -3). Due to these encouraging findings, the trial will be expanded to gain greater safety and activity experience with NEXI-002. Updated data will be available.

The virus is rapidly cleared from healthy tissues, and it does not cause damage to vital organs. The results support the initiation of a phase 1 dose-escalation trial, where melanoma patients receiving a tumor-infiltrating lymphocyte therapy are treated with TILT-123 (NCT04217473).

Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. Time-to-event endpoints will be summarized by median and corresponding 95% CI using the Kaplan–Meier method. The study is actively accruing patients at sites across North America, Europe, and Asia-Pacific.

Background: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human CD20 x CD3 IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. Preliminary analyses suggest that high levels of baseline tumor-infiltrating T cells may be associated with clinical response to odronextamab. Systemic T-cell homeostasis at baseline may be a potential predictor of clinical benefit with odronextamab, and further investigation is warranted. Although baseline CD20 expression level did not correlate with efficacy, loss of CD20 expression was observed frequently in progressive disease.

Results As compared to CYAD-01, CYAD-02 cell expansion in vitro was 3-fold increased...The study evaluates three dose-levels of CYAD-02 (1x108, 3x108 and 1x109 cells/infusion), administered as a single infusion after non-myeloablative preconditioning chemotherapy (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days, CyFlu) according to a classical Fibonacci 3+3 design...This next generation NKG2D CAR T-cell product is currently investigated in the CYCLE-1 Phase I study in r/r AML/MDS patient population, a difficult to target disease due in part to the absence of truly AML-specific surface antigens, its rapid clinical progression and the absence of disease control by the CyFlu preconditioning. Both the anti-MICA and MICB shRNA hairpin and the OptimAb manufacturing process for CYAD-02 aim to improve CAR T-cell persistence and clinical responses.

The study will also evaluate overall response rate (ORR) based on IMWG response criteria, progression-free survival (PFS) and overall survival (OS), duration of response (DOR), immunogenicity of HPN217, and other exploratory endpoints related to the mechanism of action of HPN217. (NCT04184050)

Overall, oncolytic adenovirus Ad5/3-E2F-D24-hTNFa-IRES-hIL2 was able to rewire the ovarian tumor microenvironment to accommodate heightened antitumor TIL reactivity. Such effects may improve the clinical effectiveness of ACT with TILs in patients with advanced OVCA.

When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding for TNFa and IL-2, also known as TILT-123) and checkpoint inhibitors were used together in fresh urological tumor histocultures, a significant shift toward immune activity (not only tumor necrosis alpha and interleukin-2 but also interferon gamma and granzyme B) and increased T-cell trafficking signals (CXCL10) was observed...To conclude, when an engineered oncolytic adenovirus was utilized to modify the tumor microenvironment towards what meta-analyses have pointed as predictive markers for checkpoint inhibitory therapy, the response to them increased synergistically. Of note, key findings were confirmed in fresh patient-derived tumor explants.

HER2 recognizing scFvs were derived from FRP5 and 4D5 (Trastuzumab), and GD2 recognizing scFvs were derived from 14G2a and humanized 3F8. The ectodomain containing the tandem arrangements of two distinct scFvs was joined to a signaling endodomain of the co-stimulatory molecules, CD28 and OX40, and a T-cell receptor zeta-chain...We have successfully screened multiple iterations of bispecific CAR ectodomains against melanoma demonstrating that the scFv as well as their sequence of tandem arrangement influences the antitumor function of modified T cells. The antitumor function of the top three candidate bispecific ectodomains identified will be further evaluated in pre-clinical animal models to determine the optimal construct for clinical development.

No abstract available

REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. This study is currently open to enrollment. Research Funding: Regeneron Pharmaceuticals Inc.

P1, N=15, Recruiting, TILT Biotherapeutics Ltd. | Not yet recruiting --> Recruiting

P3, N=330, Recruiting, Sinocelltech Ltd. | Not yet recruiting --> Recruiting

P2, N=103, Recruiting, Sinocelltech Ltd. | Not yet recruiting --> Recruiting

ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560)...Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707... Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4.

The use of genetically modified T cells expressing WT1-specific α/β T cell receptors can re-direct T cell specificity via the recognition of intracellular peptides presented by MHC molecules on the malignant cell surface...Patients received minimal conditioning with fludarabine and methylprednisolone prior to transfer of transduced T cells... This is the second reported phase I/II clinical trial of autologous WT1-TCR gene-modified T cells for treatment of AML and MDS in a high-risk cohort of patients not suitable for alloSCT. We have shown that the WT1-TCR T cells demonstrated a strong safety profile without detectable on-target, off-tumour toxicity and no severe adverse events in the ten patients treated. An important cause of treatment failure for adoptive cellular therapies is the lack of persistence of transferred T cells leading to loss of disease specific effects.

Hence, we hypothesized that an oncolytic adenovirus expressing Tumour Necrosis Factor (TNF)-alpha(a) and Interleukin (IL)-2 (Ad5/3-E2F-D24-hIL-2-IRES-TNFa; TILT-123) could overcome this by generating a proinflammatory microenvironment and reinvigorating TIL anti-tumour activity... These data illustrate the potential of oncolytic adenovirus coding for TNFa and IL-2 to rewire the ovarian tumour microenvironment for effective TIL anti-tumour reactivity. This approach may improve the efficacy of adoptive TIL therapy in ovarian cancer patients, thus warranting further clinical investigation.Legal entity responsible for the study: TILT Biotherapeutics Ltd. Funding: TILT Biotherapeutics Ltd.