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Open label, single arm treatment with bbT369

bbT369 is a genetically modified autologous T cell immunotherapy product consisting of T cells that are transduced with a single lentiviral vector (LVV) to express anti-CD79a and anti-CD20 chimeric antigen receptors (CARs) and transfected with an mRNA encoding the CBLB-targeting megaTAL enzyme to edit the CBLB gene, suspended in a cryopreservative solution.

bbT369

Clinical Trials Office

David Miklos, MD, PhD

Michael Tees, MD

Marissa Folsom

Ian Flinn, MD

Anna Truppel-Hartmann, MD

A Phase 1/2 Study of bbT369, a dual targeting CAR T cell drug product with a gene edit, in Relapsed and/or Refractory B cell Non-Hodgkin's Lymphoma.

This is a non-randomized, open label, multi-site Phase 1/2 study. This first-in-human Phase 1/2 Study CRC-403 will evaluate the safety and efficacy of bbT369 in subjects with relapsed and/or refractory B cell non-Hodgkin's lymphoma (NHL). Phase 1 will be a dose escalation, up to a planned four dose levels. After establishing MTD, Phase 2 will enroll subjects with B cell NHL in 2 cohorts: CAR T exposed subjects (Cohort 1) and CAR T naïve subjects (Cohort 2). A long-term follow-up is planned, in which subjects who received bbT369 will be followed for up to 15 years after drug product infusion to evaluate for safety and continued efficacy.

A Study of bbT369 in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)

A Phase 1/2 Study of bbT369, a Dual Targeting CAR T Cell Drug Product With a Gene Edit, in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)

2seventy bio

Respiratory Tract (Lung and Bronchial) Diseases

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Antineoplastic Agents

Antirheumatic Agents

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Cyclophosphamide

Fludarabine

Fludarabine phosphate

Pembrolizumab

Aldesleukin

Interleukin-2

Mesna

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Dose Escalation/Expansion Cohort

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin

Dose Expansion with Maintenance Therapy Cohort

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin

Maintenance pembrolizumab during follow-up

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +recommended phase II dose (from phase I) of CISH inactivated TIL + high-dose aldesleukin

May include maintenance pembrolizumab during follow-up

PD-L1 positive is defined as tumors with a PD-L1 Tumor Proportion Score (TPS) ≥ 1%.

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +recommended phase II dose (from phase I) of CISH inactivated TIL + high-dose aldesleukin

May include maintenance pembrolizumab during follow-up

Day -7 to Day -3 : Fludarabine 25 mg/m\^2/dose as a 1 hour intravenous infusion per institutional guidelines once a day for 5 doses beginning on Day -7. Fludarabine will be started approximately 1 to 2 hours after the cyclophosphamide on Day -6 and Day -5.

Day -6 and Day -5: Cyclophosphamide 60 mg/kg/dose as a 2 hour intravenous infusion with Mesna 15 mg/kg/dose, 1st dose prior to Cyclophosphamide infusion then at 3,6,9 and 12 hours later.

Day 0 : Each bag of autologous CISH inactivated TIL for infusion will be administered intravenously (IV) on the Patient Care Unit over 10-20 minutes at assigned dose level.

CISH Inactivated TIL

Days 1-4 : Aldesleukin at 720,000 U/kg as an intravenous infusion, every 8 -12 hours but, no more than 24 hours apart as tolerated for up to 6 doses.

Administered as maintenance therapy in some patients starting at first follow-up (400 mg/dose starting Day 28 /Week 4 then every 6 weeks thereafter until disease progression, unacceptable toxicity, or up to 24 months)

Emil Lou, MD, PhD

Erminia Massarelli, MD, PhD, MS

A clinical trial to assess the safety and efficacy of genetically-engineered Tumor Infiltrating Lymphocytes (TIL) in which the intracellular immune checkpoint CISH has been inhibited using CRISPR gene editing for the treatment of Metastatic Non-small Cell Lung Cancer (NSCLC).

Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in melanoma, but also in non-small cell lung cancer (NSCLC). Combination cell surface checkpoint inhibitor therapy has also been employed in an attempt to enhance the efficacy of these cell therapies. Genetic engineering of T cells to further increase anti-tumor activity is now possible.

CISH (Cytokine-induced SH2 protein) is a novel intra-cellular immune checkpoint and an important negative regulator of T-cell signaling and function. The inhibition of CISH in mouse anti-tumor lymphocytes results in a marked increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice.

Additionally, data in genetically-engineered, neoantigen-specific human T cells in which CISH was inhibited, showed enhanced TCR functional avidity and increased ability of these T cells to detect cancer specific mutations and mount robust polyfunctional cytokine immune responses against their cognate cancer antigens. Thus, these T cells appear to have a significant advantage in inducing anti-tumor responses compared to wild-type anti-tumor lymphocytes.

The researchers have developed and optimized a CRISPR/Cas9 based strategy for precise and efficient genetic engineering in primary human T-cells without sacrificing cell viability or function, allowing for inhibition of a heretofore undruggable intracellular checkpoint.

Thus, in this protocol, the researchers propose to inhibit the gene encoding the intracellular checkpoint target CISH in TIL from patients with metastatic NSCLC whose tumors are PD-L1 negative or positive in order to evaluate the safety and efficacy of genetically engineered T cell therapy in the setting of novel checkpoint inhibition .

CISH Inactivated TILs in the Treatment of NSCLC

A Phase 1/2 Trial (CheckCell-2) in Patients With Metastatic Non-small Cell Lung Cancer (NSCLC) Administering Tumor-Infiltrating Lymphocytes (TILs) in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System

Safety by type, incidence, severity, seriousness, and relation of study treatment of AEs, DLTs, and laboratory abnormalities. Initial efficacy per RECIST v1.1

Length of time that target lesion(s) continue to respond to treatment without growing or spreading

Percentage of combined patients who achieve complete response, partial response and stable disease

Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST v1.1 criteria

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of bbT369 in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)	NCT05169489	Diffuse Large B...	bbT369	18 Years -	2seventy bio
A Study of bbT369 in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)	NCT05169489	Diffuse Large B...	bbT369	18 Years -	2seventy bio
CISH Inactivated TILs in the Treatment of NSCLC	NCT05566223	Carcinoma, Non-... Metastatic Non ... Stage IV Non-sm... Squamous Cell L... Adenocarcinoma ... Large Cell Lung...	Fludarabine Cyclophosphamid... CISH Inactivate... Aldesleukin Pembrolizumab	18 Years - 75 Years	Intima Bioscience, Inc.

Spots Global Cancer Trial Database for gene edit

Every month we try and update this database with for gene edit cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for gene edit

Every month we try and update this database with for gene edit cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for gene edit cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.