CAR T-cell Therapy for Blood Cancer

Overseen By Abramson Cancer Center Clinical Trials Service

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Active infections, Cardiovascular disability, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Varies by dose level

72 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial aims to find the safest dose of specially modified immune cells for patients with certain types of cancers that have a specific marker. These cancers include Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Acute Lymphoblastic Leukemia. The modified cells are designed to seek out and destroy cancer cells with this marker.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should not depend on systemic steroids or immunosuppressant medications, which might imply some medications need to be adjusted or stopped.

What data supports the effectiveness of the treatment huCART19-IL18 for blood cancer?

CAR T-cell therapy, which involves modifying T cells to target cancer cells, has shown success in treating blood cancers like B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma by targeting the CD19 protein on cancer cells. This suggests that similar treatments, like huCART19-IL18, could also be effective for blood cancers. ^{1 2 3 4 5}

What is known about the safety of CAR T-cell therapy for blood cancer?

CAR T-cell therapy can be effective for blood cancers but may cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurologic toxicity (nerve-related side effects). Some patients experience life-threatening toxicities, and rare but fatal events like hemophagocytic lymphohistiocytosis (a severe immune system reaction) and disseminated intravascular coagulation (a blood clotting disorder) have been reported. Safety strategies are being developed to reduce these risks. ^{6 7 8 9 10}

What makes the treatment huCART19-IL18 unique for blood cancer?

The huCART19-IL18 treatment is unique because it combines CAR T-cell therapy, which uses modified immune cells to target cancer, with IL-18, a molecule that can enhance immune response, potentially offering a more powerful approach against blood cancers compared to standard CAR T-cell therapies. ^{4 7 11 12 13}

Research Team

Jakub Svoboda, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

Adults with CD19+ cancers like various leukemias and lymphomas, who have active disease despite previous treatments. They must be over 18, in fairly good health (ECOG 0 or 1), with decent organ function and no severe heart issues. Active infections or autoimmune diseases are deal-breakers, as is recent use of certain immune drugs.

Inclusion Criteria

I cannot use or have not responded to standard CAR T cell therapy.

- Creatinine ≤ 1.6 mg/dl

My condition worsened or didn't improve after a stem cell transplant.

Exclusion Criteria

I have a history of optic neuritis or an immune-related disease affecting my brain or spinal cord, not related to cancer.

I am receiving treatment for ongoing GVHD.

I do not currently have active brain or spinal cord disease, or it has been successfully treated.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Varies by dose level

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• huCART19-IL18

Trial Overview The trial is testing the safety of a new cell therapy called huCART19-IL18 for blood cancers that have a marker called CD19. The goal is to find the highest dose people can take without serious side effects.

Participant Groups

Group I: Cohort D: NHL Experimental Treatment 1 Intervention

7x10\^6 huCART19-IL18 as a single intravenous (IV) infusion or slow IV push

Group II: Cohort D: ALL Experimental Treatment 1 Intervention

7x10\^6 huCART19-IL18 as a single intravenous (IV) infusion or slow IV push

Group III: Cohort C: ALL Dose Level 5 (DL5) Experimental Treatment 1 Intervention

3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group IV: Cohort C: ALL Dose Level 4 (DL4) Experimental Treatment 1 Intervention

7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group V: Cohort C: ALL Dose Level 3 (DL3) Experimental Treatment 1 Intervention

3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group VI: Cohort C: ALL Dose Level 2 (DL2) Experimental Treatment 1 Intervention

7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group VII: Cohort C: ALL Dose Level 1b (DL1b) Experimental Treatment 1 Intervention

3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 2.

Group VIII: Cohort B: CLL Dose Level 5 (DL5) Experimental Treatment 1 Intervention

3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group IX: Cohort B: CLL Dose Level 4 (DL4) Experimental Treatment 1 Intervention

7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group X: Cohort B: CLL Dose Level 3 (DL3) Experimental Treatment 1 Intervention

3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XI: Cohort B: CLL Dose Level 2 (DL2) Experimental Treatment 1 Intervention

7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XII: Cohort B: CLL Dose Level 1b (DL1b) Experimental Treatment 1 Intervention

3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 2.

Group XIII: Cohort A: NHL Dose Level 5 (DL5) Experimental Treatment 1 Intervention

3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XIV: Cohort A: NHL Dose Level 4 (DL4) Experimental Treatment 1 Intervention

7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XV: Cohort A: NHL Dose Level 3 (DL3) Experimental Treatment 1 Intervention

3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XVI: Cohort A: NHL Dose Level 2 (DL2) Experimental Treatment 1 Intervention

7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XVII: Cohort A: NHL Dose Level 1b (DL1b) Experimental Treatment 1 Intervention

3x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XVIII: Cohort A: NHL Dose Level 1a (DL1a) Experimental Treatment 1 Intervention

3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push

Group XIX: Cohort A: NHL Dose Level -1 (DL-1) Experimental Treatment 1 Intervention

7x10\^5 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 1a.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

BlueWhale Bio

Collaborator

BlueWhale Bio (Cohort D only)

Collaborator

Findings from Research

CAR-T cell therapy has shown effectiveness in treating CD19-positive blood cancers, indicating its potential as a promising treatment option for aggressive tumors that have not responded well to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Prospective in CAR T-Based Therapy for Solid and Hematological Malignancies. Marei, HE., Cenciarelli, C.[2023]

Adoptive cellular therapy using CAR-modified T cells targeting CD19 has shown significant clinical efficacy in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in both children and adults, with some patients also benefiting from treatment for chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL).

Current research is expanding the use of CAR T-cell therapies to other cancers, including multiple myeloma and solid tumors, while also addressing challenges such as severe cytokine release syndrome and neurologic toxicities associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. Geyer, MB., Brentjens, RJ.[2022]

Chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells show promise in treating blood cancers, particularly with CD19-CAR-T cells demonstrating strong clinical responses in B-cell malignancies.

To enhance the effectiveness and safety of these therapies, researchers are exploring new antigens, improved T cell culture methods, and better administration protocols to address issues like treatment failure and toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming key challenges in cancer immunotherapy with engineered T cells. Arcangeli, S., Mestermann, K., Weber, J., et al.[2021]

Chimeric antigen receptor (CAR) therapy, particularly targeting CD19, has shown significant efficacy in treating patients with chemorefractory B cell malignancies, leading to its potential regulatory approval as a cell-based immunotherapy.

While CAR therapy is effective, it is associated with toxicities such as cytokine release syndrome, neurotoxicity, and B cell aplasia, which require careful management in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biology and clinical application of CAR T cells for B cell malignancies. Davila, ML., Sadelain, M.[2023]

Genetically modified T cells expressing chimeric antigen receptors (CAR) targeting the CD19 antigen have shown promise in early-phase clinical trials for treating tumors in patients who do not respond to standard therapies.

Despite some successes, not all patients achieve complete responses, highlighting the need for further research into the mechanisms of treatment failure and the potential for improving the effectiveness of CAR T cell therapies, especially for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Driving CAR-based T-cell therapy to success. Jena, B., Moyes, JS., Huls, H., et al.[2021]

CAR-T cell therapy has shown great promise in treating hematological cancers, with two Anti-CD19 CAR-T therapies already approved for CD19-positive leukemia and lymphoma.

However, the therapy can cause serious side effects like cytokine release syndrome and on-target off-tumor toxicity, leading to some patients discontinuing treatment; researchers are exploring various safety strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Yu, S., Yi, M., Qin, S., et al.[2020]

In a phase I clinical trial involving 20 patients with B-cell lymphoma, 55% achieved complete remission using the new anti-CD19 CAR T-cell therapy Hu19-CD828Z, demonstrating its effectiveness against lymphoma.

Hu19-CD828Z therapy resulted in significantly lower rates of severe neurologic toxicity (5%) compared to the previously tested FMC63-28Z therapy (50%), likely due to reduced cytokine release associated with the Hu19-CD828Z CAR design.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. Brudno, JN., Lam, N., Vanasse, D., et al.[2021]

CD19+ CAR T-cells have shown high effectiveness against various cancers, but their complete risk profile, including complications, was not fully understood during initial clinical trials.

Emerging evidence from post-approval studies reveals significant complications associated with CD19+ CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, indicating that these therapies can affect multiple organ systems and may lead to long-term health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. Penack, O., Koenecke, C.[2020]

CAR-T cell therapy has significantly improved treatment outcomes for patients with relapsed and refractory hematologic cancers, but it can also lead to serious toxicities, which are primarily caused by T-cell activation and interactions with non-cancerous cells.

The review emphasizes the need for early recognition and management of CAR-T related toxicities, as well as the potential for expanding CAR-T therapies to target solid tumors in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management and Prevention of Cellular-Therapy-Related Toxicity: Early and Late Complications. Mucha, SR., Rajendram, P.[2023]

A systematic analysis of CAR T-cell therapy adverse events revealed 5,112 reports of hematotoxicity, highlighting significant under-reporting of severe conditions like hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulation (DIC), which have high mortality rates of 69.9% and 59.6%, respectively.

The study identified 23 hematologic adverse events that were significantly over-reported compared to the general database, emphasizing the need for increased awareness and monitoring of these rare but potentially fatal toxicities in CAR T therapy patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. Song, Z., Tu, D., Tang, G., et al.[2023]

In a study of 145 adult patients undergoing anti-CD19 CAR T cell therapy, 31 patients experienced major cardiovascular events (MACE) within a median of 11 days post-infusion, highlighting a significant risk of cardiovascular complications associated with this treatment.

The analysis identified that higher baseline creatinine levels and severe cytokine release syndrome (Grade 3 or 4) were independently linked to an increased risk of MACE, suggesting the need for careful cardiovascular monitoring in patients receiving CART19 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study. Lefebvre, B., Kang, Y., Smith, AM., et al.[2022]

Chimeric antigen receptor-modified T cells (CAR-Ts) are a promising new treatment for hematological malignancies, showing powerful efficacy against tumor cells by targeting specific cancer-associated antigens.

The review discusses the CAR-T manufacturing process and highlights ongoing clinical trials for various blood cancers, including acute lymphoblastic leukemia and multiple myeloma, indicating a growing interest and development in this area of immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for hematological malignancies: Current status and new insights in chimeric antigen receptor T cells. Allegra, A., Innao, V., Gerace, D., et al.[2018]

CD19-targeted CAR-T therapy shows a high efficacy in treating refractory B-cell malignancies, with a complete remission rate of 55% and a partial remission rate of 25% based on a meta-analysis of 19 studies involving 391 patients.

While the treatment is effective, it is associated with manageable side effects, including fever (62%), hypotension (22%), and acute renal failure (24%), with no reported deaths due to toxicity, indicating a need for improved safety strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive Immunotherapy for B-cell Malignancies Using CD19- Targeted Chimeric Antigen Receptor T-Cells: A Systematic Review of Efficacy and Safety. Hao, L., Li, T., Chang, LJ., et al.[2019]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Recent Prospective in CAR T-Based Therapy for Solid and Hematological Malignancies. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Overcoming key challenges in cancer immunotherapy with engineered T cells. [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

Biology and clinical application of CAR T cells for B cell malignancies. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Driving CAR-based T-cell therapy to success. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Management and Prevention of Cellular-Therapy-Related Toxicity: Early and Late Complications. [2023]

10. Italy pubmed.ncbi.nlm.nih.gov

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for hematological malignancies: Current status and new insights in chimeric antigen receptor T cells. [2018]

13. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Adoptive Immunotherapy for B-cell Malignancies Using CD19- Targeted Chimeric Antigen Receptor T-Cells: A Systematic Review of Efficacy and Safety. [2019]