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Phase 1 will evaluate the safety of co-administration of CART22-65s with huCART19 in patients who experienced a disease relapse after prior CAR T cell therapy. There is no planned dose escalation but a dose-deescalation will be made based on the incidence of Dose Limiting Toxicities

If at least one dose level of phase 1 is determined to be safe, the phase 2 dose expansion phase of the trial will be opened to enrollment. Subjects will receive the highest dose of CART 22-65s and huCART19 cells that were determined to be safe. 2 cohorts are planned: Cohort A (relapsed/refractory, CAR T cell naïve) \& Cohort B (prior treatment with a prior CAR T cell product).

CART22-65s are autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity for CD22 linked to an intracellular signaling molecule consisting of a tandem signaling domain comprised of the TCRζ signaling module linked to the 4-1BB costimulatory domain

Autologous, humanized anti-CD22 CAR T cell therapy (CART22-65s)

HuCART19 cells are autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity for CD19 linked to an intracellular signaling molecule consisting of a tandem signaling domain comprised of the TCRζ signaling module linked to the 4-1BB costimulatory domain

Autologous, humanized anti-CD19 CAR T cell therapy (huCART19)

Melissa Varghese

Laura Shinehouse

Regina Myers, MD

This study will evaluate the safety and efficacy of administering two CAR T cell products, huCART19 and CART22-65s, in children with advanced B cell Acute Lymphoblastic Leukemia (B-ALL).

CD19-targeted CAR T cell therapy has transformed the treatment landscape for children and young adults with chemo-refractory or relapsed B cell Acute Lymphoblastic Leukemia (B-ALL). Despite remarkable initial response rates, approximately 50% of pediatric patients experience a subsequent disease relapse. The prognosis for these patients is dismal with a median survival of less than one year from the time of post-CART19 relapse. The primary mechanisms contributing to CART19 failure include CD19-antigen escape and loss of CAR T cell surveillance due to short CART persistence. This study aims to counter each driver of relapse by co-administering two next-generation CAR T cell products: an anti-CD22 CART (CART22-65s), designed to overcome CD19-antigen escape; and a humanized anti-CD19 CART (huCART19), designed to overcome immune-mediated rejection of murine CART19.

Co-administration of CART22-65s and huCART19 for B-ALL

Use of Autologous Anti-CD22 CAR T Cells (CART22-65s) Co-administered With Humanized Anti-CD19 CAR T Cells (huCART19) in Children and Young Adults With Relapsed or Refractory B-ALL

The safety of the administering CART22-65s and huCART19 will be measured by the monitoring the frequency and severity of adverse events in patients with advanced or refractory B-Cell Acute Lymphoblastic Leukemia or B Cell Lymphoblastic Lymphoma (B-LLy), including those previously treated with cell therapy.

The efficacy of CART22-65s and huCART19 co-administration will be measured by the evaluating the overall response rate in patients with advanced or refractory B cell hematologic malignancies, including those previously treated with cell therapy.

The manufacturing feasibility of manufacturing both CART22-65s and huCART19 will be measured by the percentage of manufactured products that do not meet release criteria for vector transduction efficiency, T cell product purity, viability, sterility or due to tumor contamination.

Anti-tumor response due to CART22-65s and huCART19 co-administration will be measured by negative minimal residual disease (MRD) as measured by multiparameter flow cytometry at day 28.

1-year Event-Free Survival (EFS) in subjects with relapsed/refractory B-ALL (Cohort A) and in subjects with poor response to prior B cell directed engineered cell therapy (Cohort B)

1-year relapse-free survival (RFS) rate in CAR-naïve subjects with relapsed/refractory B-ALL (Cohort A) and in CAR-exposed subjects with poor response to prior B cell directed engineered cell therapy (Cohort B)

1-year overall survival (OS) rate in CAR-naïve subjects with relapsed/refractory B-ALL (Cohort A) and in CAR-exposed subjects with poor response to prior B cell directed engineered cell therapy (Cohort B).

CART22-65s and huCART19 persistence polymerase chain reaction (or flow cytometry) analysis of whole blood to detect and quantify survival of CART2265s and huCART19 over time.

The bioreactivity of CART22-65s and huCART19 when co-administered, as measured by elevations level in any of; Uric Acid, Lactate Dehydrogenase (LDH), c-reactive protein (CRP), and cytokines (e.g.IL -10) before and after CART T cell infusions.

University of Pennsylvania

Stephan Grupp MD PhD

Chief, Cell Therapy and Transplant Section Director, Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy Medical Director, Cell and Gene Therapy Lab

The phase 1 dose escalation portion of the trial will use a standard "3+3" design to establish the recommended phase 2 dose of huCART19 cells in patients with subjects with prior treatment with CD19-directed CAR T cells. Two dose escalations of huCART19 are planned for the dose escalation phase.

If at least one dose level of the dose escalation phase is determined to be safe, the phase 2b dose expansion phase of the trial will be opened to enrollment. Subjects will receive the highest dose of huCART19 cells that were determined to be safe in the dose escalation part of the trial. 2 cohorts are planned:

* Cohort A (relapsed/refractory, CAR T cell naïve)
* Cohort B (prior treatment with CD19-directed CAR T cells)

The investigational agent in this protocol is humanized CART19 cells (huCART19). Autologous T cells will be engineered to express an extracellular single chain antibody (scFv) with specificity for CD19. This will be expected to redirect specificity of the transduced T cells for cells that express CD19, a molecule that is restricted in expression on the surface of the malignant cells and on normal B cells.

Autologous Humanized CD19-Directed Chimeric Antigen Receptor T-Cells (huCART19)

Raabia Khan, MPH

Melissa Varghese, BA

Allison Barz Leahy, MD

Stephan Grupp, MD,PhD

This study will determine the safety and efficacy of moving to a second-generation manufacturing process using the CliniMACS Prodigy platform to manufacture huCART19 cells for patients with B cell Acute Lymphoblastic Leukemia (B-ALL).

Chimeric Antigen Receptor T-Cells (CAR T) cell therapy has shifted the treatment landscape for pediatric and young adult patients with multiply relapsed and refractory B-ALL (B cell Acute Lymphoblastic Leukemia), however, the manufacturing process remains in its first generation: laborious, time-intensive, and not automated. The time and significant personnel resources in this process can result in patient safety issues - with patients growing sicker, with harder to control leukemias - in the waiting period between T cell collection and completed CAR T cell product manufacture. Use of the CliniMACS Prodigy platform, that allows for semi-automated clinical-scale processing of huCART19 cell products in a functionally closed, sterile system, rapidly, without many of the logistical burdens encountered in the first-generation manufacturing method, can help to surmount these issues. This study will determine the safety and efficacy of moving to a second-generation manufacturing process using the CliniMACS Prodigy platform to manufacture huCART19 cells.

Autologous HuCART19 T Cells Manufactured Using the CliniMACS Prodigy Platform for Pediatric B-ALL (huCART19 Prodigy)

Phase 1/2b Trial of Autologous Humanized CD19-Directed Chimeric Antigen Receptor T-Cells Manufactured Using the CliniMACS Prodigy Platform for the Treatment of Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL)

The safety of the administering Humanized Cd19-Directed Chimeric Antigen Receptor T-Cells (huCART9) will be measured by the monitoring the frequency and severity of adverse events in patients with advanced or refractory CD19+ hematologic malignancies, including those previously treated with cell therapy.

The efficacy of huCART9 will be measured by the evaluating the overall response rate in patients with advanced or refractory CD19+ hematologic malignancies, including those previously treated with cell therapy.

Manufacturing feasibility will be measured by the percentage of manufactured products that do not meet release criteria for vector transduction efficiency, T cell product purity, viability, sterility, or due to tumor contamination.

Safety of huCART19 as measured by ≥ Grade 3 toxicity rate (toxicity that is possibly attributed to huCART19) that is unmanageable, unexpected, and unrelated to chemotherapy.

For subjects with detectable disease, measure anti-tumor response due to huCART19 cell infusions, as defined by the presence of medullary (morphologic or Minimal Residual Disease (MRD-level disease) and/or extramedullary disease at 1-month post-infusion.

Overall remission rate will be measured by the proportion of treated subjects who achieve complete morphologic remission at Day 28 post huCART19 infusion.

huCART 19 cell persistence will be measured by PCR (or flow) analysis of whole blood to detect and quantify survival of huCART19 cells over time.

1-year Event-Free Survival (EFS) in subjects with relapsed/refractory B-ALL (Cohort A) and in subjects with poor response to prior B cell directed engineered cell therapy (Cohort B).

1-year Relapse-Free Survival (RFS) in subjects with relapsed/refractory B-ALL (Cohort A) and in subjects with poor response to prior B cell directed engineered cell therapy (Cohort B).

1-year Overall Survival (OS) in subjects with relapsed/refractory B-ALL (Cohort A) and in subjects with poor response to prior B cell directed engineered cell therapy (Cohort B).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Co-administration of CART22-65s and huCART19 for B-ALL	NCT05674175	B-cell Acute Ly... B Lineage Lymph...	Autologous, hum... Autologous, hum...	- 29 Years	Children's Hospital of Philadelphia
Autologous HuCART19 T Cells Manufactured Using the CliniMACS Prodigy Platform for Pediatric B-ALL (huCART19 Prodigy)	NCT05480449	B Cell Acute Ly... B Lineage Lymph...	Autologous Huma...	0 Years - 29 Years	Children's Hospital of Philadelphia
Autologous HuCART19 T Cells Manufactured Using the CliniMACS Prodigy Platform for Pediatric B-ALL (huCART19 Prodigy)	NCT05480449	B Cell Acute Ly... B Lineage Lymph...	Autologous Huma...	0 Years - 29 Years	Children's Hospital of Philadelphia
Co-administration of CART22-65s and huCART19 for B-ALL	NCT05674175	B-cell Acute Ly... B Lineage Lymph...	Autologous, hum... Autologous, hum...	- 29 Years	Children's Hospital of Philadelphia

Spots Global Cancer Trial Database for b lineage lymphoblastic lymphoma