Interius BioTherapeutics In Vivo CAR Therapy INT2104 Cleared for Phase 1 Clinical Trial in B-cell Malignancies Australia

Interius BioTherapeutics’ INT2104, an investigational lentiviral vector-based gene therapy that is intended to treat B-cell malignancies through the creation of CD20-directed chimeric antigen receptor (CAR) T-cells and CAR natural killer (NK) cells in vivo, has received Human Research Ethics Committee (HREC) approval and clinical trial notification (CTN) clearance from Australia’s Therapeutic Goods Administration (TGA).¹

In light of the CTN clearance, Interius expects to initiate plans for a phase 1 clinical trial (INVISE, Injectable Vectors for In Situ Engineering) for INT2104 within the final quarter of 2024. The global, multicenter, open-label trial will begin with a dose-escalation portion and then move onto a dose confirmation portion once a dose has been selected. In INVISE adults with refractory/relapsing B-cell malignancies will receive treatment with a single dose of INT2104, which is administered via intravenous infusion and does not require lymphodepletion or special equipment/training to deliver. Interius expects that key milestones from INVISE may be reported in Q1 2025.

“Receiving HREC approval and CTN clearance for our first clinical trial is a significant milestone for Interius,” Phil Johnson, MD, the president and chief executive officer of Interius, said in a statement.¹ “We are very pleased that the regulators have approved the start of our first-in-human clinical trial for INT2104. The approval allows us to enroll patients in our first clinical study and recognizes the potential of our novel in vivo targeted gene therapy candidate, INT2104, to address an unmet medical need for patients with B-cell malignancies. We look forward to continuing to work closely with the TGA and other regulators in the future to bring this innovative therapy to patients as quickly as possible.”

INT2104 is specifically targeted at CD7-positive T-cells and NK cells, which it is intended to transduce with the CAR transgene in order to produce effector CAR T-cells and CAR-NK cells. The targeting specificity of the vector is accomplished via engineered fusogen and binder components.² Preclinical data demonstrating the potential of INT2104 were previously presented at the Cellicon Valley 2023 Meeting, held June 21 to 23, in Philadelphia, PA.³ Complete tumor clearance was reported in mouse models of systemic lymphoma following treatment with the viral vector across a wide dose range. Furthermore, when INT2104 was used in nonhuman primates (NHPs), the NHPs showed significant depletion of B-cells with no toxicity reported. In 1 individual NHP, the B-cell depletion was noted to have been maintained for more than 6 months posttreatment.

In vitro preclinical work also demonstrated dose dependent transduction of CD7-positive cells, and a lack of transduction when INT2104 was administered to CD7-negative B-cell lines.² Furthermore, transduction of both CD7-positive T-cells and CD7-positive NK cells was observed, and the CAR-positive cells demonstrated dose-dependent killing of B-cells when cocultured with B-cell tumor targets. Additional in vitro testing in 6 B-cell tumor lines and primary peripheral blood mononuclear cells from patients with B-cell malignancies indicated that off-target transduction by B-cells treated with INT2104 did not occur.

“The company’s preclinical data address 3 critical questions: Does it work? Can you make it? Is it safe? We are thrilled that the answer to each of these questions is yes based on extensive animal model work, including dosing of over 20 cynomolgus macaques, with a vector dose equivalent or exceeding the highest proposed human dose,” Johnson said in a June 2023 statement.³ “In all models we have observed no signs of cytokine release syndrome or neurotoxicity, no clinical symptoms, and no laboratory abnormalities.”

REFERENCES
1. Interius Biotherapeutics receives HREC approval and CTN clearance from the TGA to commence a phase 1 clinical trial for its first-in-class in vivo CAR therapeutic for B cell malignancies. News release. Interius BioTherapeutics. July 9, 2024. Accessed July 13, 2024. https://interiusbio.com/2024/07/interius-biotherapeutics-receives-hrec-approval-and-ctn-clearance-from-the-tga-to-commence-a-phase-1-clinical-trial-for-its-first-in-class-in-vivo-car-therapeutic-for-b-cell-malignancies-will-initiate/
2. Andorko JI, Gill S, Johnson PR. Targeted in vivo generation of CAR T and NK cells utilizing an engineered lentiviral vector platform. Presented at the Cellicon Valley 2023 Meeting, held June 21 to 23, in Philadelphia, PA.
3. Interius Biotherapeutics highlights strong preclinical data supporting in vivo chimeric antigen receptor (CAR) vector evaluation in clinic. News release. InteriusBioTherapeutics. June 21, 2023. Accessed July 13, 2024. https://interiusbio.com/2023/06/interius-biotherapeutics-highlights-strong-preclinical-data-supporting-in-vivo-chimeric-antigen-receptor-car-vector-evaluation-in-clinic/