Glioblastoma multiforme or GBM, the most common primary brain tumor in adults, is associated with a poor prognosis and is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. [1]

In trying to meet the unmet medical need, clinical-stage biopharmaceutical company IN8bio, which has developed an number of innovative gamma-delta (γδ) T-cell therapies utilizing its proprietary DeltEx platform, shared updates from the ongoing Phase 1 clinical trial of INB-200 which is being developed to treat GBM.

The investigational drug is an autologous drug resistant immunotherapy or DRI, which  consists of gamma-delta T-cells that have been genetically engineered to be chemotherapy resistant. As a result, the drug can be administered concurrently with alkylating chemotherapeutic agents, including temozolomide (Temodar®; Merck & Co).

Platform technology
Gamma-delta T cells are a specialized population of T-cells that possess unique properties, including the ability to differentiate between healthy and diseased tissue. IN8bio proprietary DeltEx platform is designed to overcome many of the challenges associated with the expansion, genetic engineering, and scalable manufacturing of gamma-delta T-cells.

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The technology platform uses allogeneic, autologous, and genetically modified approaches to develop cell therapies, designed to effectively identify and eradicate tumor cells. This approach allows us to expand the cells ex vivo to administer a potentially therapeutic dose to patients, harnessing the unique properties of gamma-delta T cells, including their ability to broadly recognize cellular stress signals on tumor cells.

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Using their platform technology, IN8bio has developed a pipeline of innovative allogeneic, autologous and/or genetically modified product candidates designed to effectively target and potentially eradicate disease and improve patient outcomes.

The company is currently conducting two investigator-initiated Phase 1 clinical trials for its lead gamma-delta T cell product candidates. INB-200, for the treatment of newly diagnosed glioblastoma, and INB-100, for the treatment of patients with leukemia undergoing hematopoietic stem cell transplantation.

Study
This clinical trial, conducted in patients newly diagnosed with glioblastoma multiforme (GBM), is the first and most clinically advanced trial to use genetically modified gamma-delta T-cells and includes a multi-dose escalation regimen.

For Cohort 1 of the study, accrual and treatment is complete with three patients having received a single dose of DeltEx DRI via intracranial infusion concurrent with maintenance TMZ administration. Cohort 2 is currently recruiting and treating patients, with one patient having completed all three doses administered intracranially at 28-day intervals concurrent with maintenance temozolomide.

The Phase 1 clinical trial of INB-200 involves the first single- and multiple-dosed patients with genetically modified gamma-delta T cells in any indication.

Safety profile
Based on the preliminary results of the study, INB-200 has had a manageable safety profile in all four patients treated to date. The investigators did not observe dose limiting toxicity (DLT), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or treatment-related serious adverse events (SAEs). The data to-date indicate promising progression=free survival (PFS) and overall survival (OS), which will continue to be assessed on an on-going basis, with additional data anticipated at medical meetings later this year along with comprehensive biological correlative data.

“Patients diagnosed with GBM have poor prognoses with a median survival of 14.6 to 16.6 months and PFS of approximately 4 to 6.9 months. The data reported today suggest that INB-200 may have the potential to extend both progression-free and overall survival compared with standard-of-care in the front-line setting,” explained Trishna Goswami, MD, Chief Medical Officer at IN8bio.

“We believe that the combination of our DRI technology and the potential to administer multiple doses of INB-200 could lead to improved efficacy results by making our gamma-delta T cells resistant to chemotherapy induced cell death, potentially permitting prolonged and more efficient tumor killing. This approach may overcome the limited efficacy observed in clinical trials of other cellular therapies in patients with solid tumors,” she added.

“We are pleased to see that INB-200 has continued to be well-tolerated in both the single and multiple-dose treated patients to-date,” said principal investigator, L. Burt Nabors, MD at the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham (UAB).

“GBM is one of the most difficult cancers to treat, with an urgent need for new therapies. One of the significant hurdles to the use of cellular therapies in solid tumors is the impact of chemotherapies on immune cells, which has been uniquely addressed in the engineering of the DeltEx DRI cells,” Nabors concluded.

Treatment to-date
Four patients have been treated to-date. In cohort 1, all have patients exceeded their expected PFS interval, with an encouraging trend in OS based on standard-of-care for their respective age and methylguanine-DNA methyltransferase (MGMT) status [1][2][3]

One of the patients participating in the study remains alive at 17 months post-treatment, having exceeded their expected PFS and OS. A second patient survived for 15.6 months, with a PFS of 8.3 months, and died from an unrelated medical event without further progression. The third patient in cohort 1 exceeded predicted PFS and died at 9.6 months due to progression.

In cohort 2, the first patient to complete all three doses has stable disease at 6.9 months and remains in follow-up. An earlier patient enrolled in cohort 2 completed two doses of INB-200 but died due to an acute cardio-pulmonary event without further disease progression. This was reviewed by the data safety monitoring board (DSMB) and the FDA who deemed the event unlikely to be related to therapy, and the study was allowed to continue uninterrupted. Neither patient dosed in cohort 2 experienced any infusion reactions, CRS, DLTs, or ICANS. Patient recruitment and treatment are ongoing with anticipated completion of enrollment in 2022.

INB-200 is an investigator initiated, open-label Phase 1 clinical trial evaluating IN8bio’s DeltEx DRI therapy in newly diagnosed GBM patients. Patients in cohort 1 received a single dose of INB-200, while patients in cohort 2 receive three doses at 28-day intervals and patients in cohort 3 are planned to receive six doses at 28-day intervals. All doses are given concurrently with maintenance TMZ and are intended to eliminate residual cancer during the vulnerable period of chemotherapy-induced tumor injury, when immune stress ligand expression is upregulated. The primary endpoints of this Phase 1 trial are safety and tolerability, with secondary endpoints based on biologic response, progression free and overall survival.

Clinical trials
Novel Gamma-Delta (γδ)T Cell Therapy for Treatment of Patients With Newly Diagnosed Glioblastoma (DRI) – NCT04165941
Expanded/Activated Gamma Delta T-cell Infusion Following Hematopoietic Stem Cell Transplantation and Post-transplant Cyclophosphamide – NCT03533816

Highlights of prescribing information
Temozolomide (Temodar®; Merck & Co)(Prescribing Information)

References
[1] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330. PMID: 15758009.
[2] Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. doi: 10.1056/NEJMoa043331. PMID: 15758010.
[3] Perry JR, Laperriere N, O’Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. doi: 10.1056/NEJMoa1611977. PMID: 28296618.

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