Armored CAR T Cells for Blood Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Autoimmune disease, HIV, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2-7 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating certain blood cancers using modified T cells, a type of immune cell. The goal is to determine a safe dose and assess how these modified cells affect the cancer. It targets individuals whose cancer has returned or not responded to standard treatments. For those with blood cancers like CLL or DLBCL where treatments have failed, this trial might be suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that a new treatment using EGFRt/19-28z/4-1BBL CAR T cells has been tested for safety in blood cancer patients. In earlier studies, most participants tolerated the treatment well. Some experienced side effects such as tiredness, fever, or low blood cell counts, but these were usually manageable. This treatment uses specially modified immune cells to attack cancer cells.

Serious side effects, like a strong immune reaction called cytokine release syndrome, can occur but are less common and often treatable. As this is a Phase 1 trial, the main goal is to determine a safe dose. Although data from participants is limited, it indicates the treatment is safe enough for human testing. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about EGFRt/19-28z/4-1BBL CAR T cells because they bring a new approach to treating blood cancer. Unlike traditional chemotherapies or standard CAR T-cell therapies that might only target one aspect of the cancer, this treatment is engineered to target CD19 on cancer cells and includes a co-stimulatory ligand, 4-1BBL, to enhance the T cells' ability to persist and fight cancer more effectively. Additionally, the treatment incorporates the EGFRt safety system, which provides a built-in safety switch to help manage potential side effects. This innovative combination aims to improve the effectiveness and safety of CAR T-cell therapy for patients.

What evidence suggests that EGFRt/19-28z/4-1BBL CAR T cells might be an effective treatment for blood cancer?

Research has shown that a new treatment using EGFRt/19-28z/4-1BBL CAR T cells, which participants in this trial will receive, shows promise for treating blood cancers. These specially designed cells target a protein called CD19, found on many cancerous B-cells. Studies indicate that this therapy can be effective for patients whose blood cancer has returned or hasn't responded to other treatments. The addition of 4-1BBL boosts the activity of these modified cells and may lead to better results. Early evidence suggests this treatment could offer a new option for patients who have tried all standard therapies without success. ^{1 2 3 6 7}

Who Is on the Research Team?

Jae Park, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with certain blood cancers like CLL, ALL, and others that have not responded to standard treatments can join. They must have a specific marker called CD19 on their cancer cells and meet health criteria such as proper kidney function, liver function, heart performance (LVEF ≥40%), and no severe active infections or autoimmune diseases.

Inclusion Criteria

My cancer affects B cells, has returned or didn't respond to treatment, and tests positive for CD19.

My lymphoma has returned after treatment, confirmed by a biopsy.

My iNHL cancer did not respond or has returned after 2 treatments.

Exclusion Criteria

My heart's pumping ability is severely reduced (EF 20% or less).

My heart's pumping ability is reduced (below 40%).

I have severe heart failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and T Cell Modification

Patients undergo leukapheresis for T cell enrichment, activation, and genetic modification using a retroviral vector encoding a CD19-targeted CAR.

2-3 weeks

Conditioning Chemotherapy

Patients receive conditioning chemotherapy prior to T cell infusion.

1 week

Treatment

Modified T cell infusions are administered following conditioning chemotherapy.

2-7 days

In-person visits for T cell infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment, including serial sampling of blood and bone marrow.

4 weeks

Multiple in-person visits for monitoring

What Are the Treatments Tested in This Trial?

Interventions

• EGFRt/19-28z/4-1BBL CAR T cells

Trial Overview

This trial is testing different doses of 'armored' CAR T cells designed to target CD19+ cancer cells in patients whose disease has returned after treatment. The study aims to find the safest dose level for these modified T cells and see how they affect the patient's body and cancer.

How Is the Trial Designed?

Group I: EGFRt/19-28z/4-1BBL CAR T cells Experimental Treatment 1 Intervention

Following enrollment, patients will undergo leukapheresis of peripheral blood for further T cell enrichment, activation and genetic modification using a retroviral vector encoding a CD19targeted CAR, the co-stimulatory ligand 4-1BBL and the EGFRt safety system (EGFRt/19-28z/4-1BBL). These T cells will be expanded and after the appropriate number of cells is generated, the modified T cells may be infused fresh or frozen for later use according to standard operation procedures. Modified T cell infusions will be administered 2-7 days following completion of the treating investigator's choice of conditioning chemotherapy. Serial sampling of blood and bone marrow will be performed following treatment to assess toxicity, therapeutic effects, and survival of the genetically modified T cells.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

Industry Sponsor

Trials

19

Recruited

3,100+

Juno Therapeutics, Inc.

Industry Sponsor

Trials

8

Recruited

810+

Published Research Related to This Trial

CAR T cell therapy has shown remarkable success in treating B-cell malignancies, but it faces significant challenges when targeting solid tumors due to the unique characteristics of their microenvironments.

Recent advancements in CAR T cell engineering aim to overcome these challenges by developing smarter CAR T cells that enhance efficacy and reduce adverse effects, paving the way for improved cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells. Elahi, R., Khosh, E., Tahmasebi, S., et al.[2019]

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

CAR T-cell therapy has shown durable remission in B-cell leukemia and lymphoma, highlighting its potential effectiveness for treating other types of cancers.

Recent advancements in CAR design and clinical application strategies aim to enhance T-cell proliferation and efficacy while minimizing toxicity, making this therapy more accessible to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity. Maus, MV., Powell, DJ.[2018]

CAR-T cell therapy has shown remarkable success in treating B-cell malignancies, but researchers are focused on improving its safety and effectiveness due to risks like cytokine release syndrome and off-target effects.

Innovative safety strategies, such as ON- and OFF-switch CARs and multi-antigen-targeting CAR-T cells, are being developed to enhance the persistence and reduce adverse events associated with CAR-T therapy, paving the way for a new generation of treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Next-Generation CAR-T Cells for Better Toxicity Management. Andrea, AE., Chiron, A., Bessoles, S., et al.[2023]

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]

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., et al.[2023]

CAR-T therapy has shown significant success in treating relapsed/refractory B-cell malignancies, utilizing genetically modified T-cells to target and eliminate cancer cells effectively.

Despite its efficacy, CAR-T therapy is associated with serious toxicities such as cytokine release syndrome and neurotoxicity, necessitating improved safety measures, especially as the therapy is being tested in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building safety into CAR-T therapy. Peters, DT., Savoldo, B., Grover, NS.[2023]

Adoptive cell therapy using CAR-modified T cells has shown promising results, achieving complete remission in patients with B cell malignancies over the long term.

There are currently around 100 ongoing clinical trials exploring CAR T cell therapies for various blood cancers and solid tumors, highlighting the rapid advancement and interest in this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The growing world of CAR T cell trials: a systematic review. Holzinger, A., Barden, M., Abken, H.[2018]

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]

CAR-engineered immune cell therapy has shown promise in treating blood cancers, but solid tumors remain challenging due to issues like immunogenicity and off-tumor toxicity, which can lead to serious side effects.

To improve the effectiveness and safety of CAR therapy for solid tumors, strategies such as regional delivery, repeated dosing, and the development of multi-targeted CAR approaches are being explored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR Based Immunotherapy of Solid Tumours-A Clinically Based Review of Target Antigens. Maher, J., Davies, DM.[2023]

CAR T cell therapy targeting CD19 has shown remarkable efficacy, achieving complete remission in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), compared to a 30% response rate with traditional chemotherapy.

The therapy involves genetically modifying T cells to express a chimeric antigen receptor, allowing them to effectively target and eliminate cancer cells, although it is important to note that there are unique toxicities associated with this treatment that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Davila, ML., Brentjens, RJ.[2023]

CAR T-cell immunotherapy, which involves genetically modifying T cells to target cancer cells, has shown promising results, especially in treating B-cell malignancies with several patients achieving complete and durable responses.

Current research is expanding CAR T-cell therapy to solid tumors, specifically targeting members of the ErbB family, indicating a potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ErbB-targeted CAR T-cell immunotherapy of cancer. Whilding, LM., Maher, J.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8144892/

CAR-T cells: Early successes in blood cancer and challenges ...

For many solid tumors, therapy with checkpoint inhibitors has shown promise. For hematologic malignancies, adoptive and engineered cell therapies are being ...

2.

researchgate.net

researchgate.net/publication/327493225_A_phase_I_trial_of_CD19-targeted_EGFRt19-28z4-1BBL_armored_chimeric_antigen_receptor_CAR_modified_T_cells_in_patients_with_relapsed_or_refractory_chronic_lymphocytic_leukemia

A phase I trial of CD19-targeted EGFRt/19-28z/4-1BBL ...

... efficacy of CAR T cell antitumor responses in solid cancers. ... 41BBL CAR T cells in patients with relapsed or refractory CD19+ hematologic malignancies.

3.

asco.org

asco.org/abstracts-presentations/ABSTRACT194568

A phase I trial of CD19-targeted EGFRt/19-28z/4-1BBL ...

... CAR T cells in ICAM-1 positive relapsed and/or refractory advanced poorly differentiated and anaplastic thyroid cancers. First Author: Samer Ali Srour. About ...

4.

cancer.gov

cancer.gov/publications/dictionaries/cancer-drug/def/autologous-egfrt-19-28z-4-1bbl-car-t-lymphocytes

autologous EGFRt/19-28z/4-1BBL CAR T lymphocytes

CD19 antigen is a B-cell specific cell surface antigen expressed in all B-cell lineage malignancies. The CD28 co-stimulatory molecule signaling domain ...

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7333410/

Recent advances in CAR-T cell engineering - PMC

... effective solution for relapsed or refractory tumors, particularly for ... The preliminary results of dual and combined CAR-T cell therapy for B cell malignancies ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06758713

Safety and Efficacy of Fourth-Generation CAR-T in the ...

... for side effects and effect of the CAR-T. Official Title. Safety and Efficacy of Fourth-Generation CAR-T in the Treatment of Hematologic Malignancies.

7.

jhoonline.biomedcentral.com

jhoonline.biomedcentral.com/articles/10.1186/s13045-020-00910-5

Recent advances in CAR-T cell engineering

CAR-T cells engineered in this manner show exciting response rates for specific hematological malignancies, and a few phenomenal targets have ...