CAR T Cells for Blood Cancers

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Roswell Park Cancer Institute

Must not be taking: T cell suppressive therapy

Disqualifiers: Pregnancy, HIV, Hepatitis B, others

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

Compensation: Varies

Number of Visits: 9

54 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of genetically engineered cells called EGFRt/19-28z/IL-12 CAR T cells, and to see how they work in treating patients with hematologic malignancies that makes a protein called CD19 (CD19-positive) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Chimeric Antigen Receptor (CAR) T-cell Therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. To improve the effectiveness of the modified T cells and to help the immune system fight cancer cells better, the modified T cells given in this study will include a gene that makes the T cells produce a cytokine (a molecule involved in signaling within the immune system) called interleukin-12 (IL-12). The researchers think that IL-12 may improve the effectiveness of the modified T cells, and it may also strengthen the immune system to fight cancer. Giving EGFRt/19-28z/IL-12 CAR T cells may be safe and tolerable in treating patients with relapsed or refractory CD19+ hematologic malignancies.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on systemic T cell suppressive therapy for conditions like active graft versus host disease or autoimmune disease, you would be ineligible for the trial. It's best to discuss your specific medications with the trial team.

What data supports the idea that CAR T Cells for Blood Cancers is an effective treatment?

The available research shows that CAR T Cells for Blood Cancers are effective, especially for certain types of blood cancers like B-cell acute lymphoblastic leukemia (B-ALL). In one study, patients with relapsed B-ALL who received CAR T cell therapy experienced rapid tumor eradication and achieved complete remission. This means their cancer was no longer detectable after treatment. Another study highlights that CAR T cell therapy has shown substantial clinical benefits in both children and adults with relapsed or hard-to-treat B-ALL, as well as some cases of chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL). These results suggest that CAR T Cells are a promising treatment option for these blood cancers, offering hope where other treatments might not be as effective. ^{1 2 3 4 5}

What safety data exists for CAR T cell therapy in blood cancers?

CAR T cell therapy, including variants like EGFRt/19-28z/IL-12 CAR T Cells, has shown substantial clinical efficacy in treating blood cancers such as B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and B-cell non-Hodgkin lymphoma (B-NHL). However, safety concerns primarily involve severe toxicities like cytokine release syndrome (CRS) and neurotoxicity. Strategies to manage these include using tocilizumab to treat severe CRS without negating the therapy's benefits. The severity of adverse events often correlates with pretreatment tumor burden, suggesting that early intervention or debulking strategies may reduce risks. Ongoing efforts aim to improve the safety and efficacy of CAR T cell therapies. ^{4 6 7 8 9}

Is the treatment EGFRt/19-28z/IL-12 CAR T Cells promising for blood cancers?

Yes, EGFRt/19-28z/IL-12 CAR T Cells are a promising treatment for blood cancers. CAR T-cell therapy has shown great success in treating blood cancers by using modified immune cells to target and destroy cancer cells. The addition of IL-12 can enhance the immune response, potentially making this treatment even more effective. ^{1 2 4 10 11}

Research Team

Francisco J. Hernandez-ILizaliturri

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

This trial is for patients with certain blood cancers (like lymphoma or leukemia) that have a protein called CD19 and haven't improved after treatment or have come back. Participants need to be in good physical shape, with no major heart, lung, kidney, liver, or mental health issues.

Inclusion Criteria

I have at least one cancer lesion that shows up on a PET scan.

AST and ALT ≤ 3 x upper limit of normal (ULN) (unless related to disease)

My oxygen levels are 90% or higher on room air.

Exclusion Criteria

I have not had a heart attack in the last 6 months.

Unwilling or unable to follow protocol requirements

I have severe heart failure.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for ECHO/MUGA, CT/PET, and biopsies

Leukapheresis

Patients undergo leukapheresis to collect T cells for modification

1 day

1 visit (in-person)

Lymphodepletion Chemotherapy

Patients receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine

3 days

3 visits (in-person)

CAR T-cell Infusion

Patients receive EGFRt/19-28z/IL-12 CAR T cells intravenously

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Weekly for 4 weeks, every 4 weeks until 24 months, every 3 months for 1 year, then annually

Treatment Details

Interventions

• EGFRt/19-28z/IL-12 CAR T Cells

Trial Overview The study tests genetically modified immune cells (EGFRt/19-28z/IL-12 CAR T cells) to see if they're safe and effective against these CD19+ blood cancers. It's an early-phase trial to find the right dose of these engineered T cells that are infused back into the patient.

Participant Groups

Group I: Cohort B (EGFRt/19- 28z/IL-12 CAR T cells, conditioning) Experimental Treatment 12 Interventions

Patients undergo leukapheresis prior to treatment and receive lymphodepletion chemotherapy with cyclophosphamide IV over 2 hours and fludarabine IV over 30 minutes on days -5, -4, and -3. Patients then receive EGFRt/19- 28z/IL-12 CAR T cells IV over 5 to 30 minutes on day 0. Patients also undergo ECHO or MUGA during screening. Patients also undergo CT or PET as well as bone marrow biopsy and aspiration and blood sample collection throughout the trial. Additionally, patients undergo a tissue biopsy during screening and on the trial.

Group II: Cohort A (EGFRt/19- 28z/IL-12 CAR T cells) Experimental Treatment 10 Interventions

Patients undergo leukapheresis prior to treatment. Patients receive EGFRt/19- 28z/IL-12 CAR T cells IV over 5 to 30 minutes on day 0. Patients also undergo ECHO or MUGA during screening. Patients also undergo CT or PET as well as bone marrow biopsy and aspiration and blood sample collection throughout the trial. Additionally, patients undergo a tissue biopsy during screening and on the trial.

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

Findings from Research

The combination of carcinoembryonic antigen (CEA) specific CAR-T cells with recombinant human IL-12 (rhIL-12) significantly enhances the activation, proliferation, and cytotoxicity of CAR-T cells against solid tumors, as shown in both in vitro and in vivo studies.

In vivo experiments demonstrated that CEA-CAR-T cells combined with rhIL-12 exhibited superior anti-tumor activity against various solid tumors, including colorectal, pancreatic, and gastric cancers, compared to CEA-CAR-T cells alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Significantly increased anti-tumor activity of carcinoembryonic antigen-specific chimeric antigen receptor T cells in combination with recombinant human IL-12. Chi, X., Yang, P., Zhang, E., et al.[2021]

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]

In a study involving five adults with relapsed B cell acute lymphoblastic leukemia (B-ALL), treatment with autologous T cells modified to express a CD19-specific CAR (19-28z) led to rapid tumor eradication and complete remissions without minimal residual disease (MRD), indicating strong efficacy of this therapy.

The treatment was generally well tolerated, although patients with higher tumor burdens experienced significant cytokine elevations, which required management with steroids, highlighting the need for monitoring and potential intervention during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Brentjens, RJ., Davila, ML., Riviere, I., et al.[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]

CAR T cell therapy has shown remarkable success in treating blood cancers, but challenges remain in effectively targeting solid tumors and certain blood malignancies.

Recent advancements in genetic engineering and the use of combination agents are being explored to enhance the efficacy of CAR T cell therapy, indicating a promising direction for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents. Park, CH.[2023]

HER2 CAR T-cell therapy shows promise for treating solid tumors, particularly in cancers like breast cancer, but it carries significant risks of severe side effects, such as cytokine release syndrome due to targeting HER2 on non-cancerous tissues.

The review highlights ongoing efforts to enhance the safety of HER2 CAR therapies through novel designs and alternative CAR host selections, aiming to minimize the risk of toxicities while maintaining therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Driving better and safer HER2-specific CARs for cancer therapy. Liu, X., Zhang, N., Shi, H.[2019]

CAR T cell therapy, specifically targeting the CD19 antigen, has shown high response rates in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), indicating its potential as a new treatment option.

Despite its effectiveness, CAR T cell therapy is associated with severe toxicities like cytokine release syndrome and neurotoxicity, which pose challenges for its widespread use and highlight the need for ongoing improvements in the technology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. Luskin, MR., DeAngelo, DJ.[2018]

In a Phase I clinical trial, 19-28z CAR T-cell therapy achieved an impressive 88% complete remission rate in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), demonstrating its efficacy as a treatment option.

While the therapy can lead to severe cytokine release syndrome (sCRS), it can be effectively managed with tocilizumab without compromising the treatment's benefits, unlike high-dose steroids which can negate the positive effects of CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer CARtography: charting out a new approach to cancer immunotherapy. Patel, JM., Dale, GA., Vartabedian, VF., et al.[2021]

CAR T cell therapy, particularly with the approval of tisagenlecleucel, has shown remarkable efficacy in treating pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia, with six therapies approved as of April 2023 for B-cell malignancies and multiple myeloma.

However, the therapy is associated with significant adverse events like cytokine release syndrome, which are more severe with higher pretreatment tumor burdens; thus, initiating therapy early or using a debulking strategy may help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From bench to bedside: the history and progress of CAR T cell therapy. Mitra, A., Barua, A., Huang, L., et al.[2023]

CAR-T cell therapy is emerging as a promising immunotherapy for hematological cancers, particularly by targeting immune checkpoint proteins on tumor cells.

The review discusses various CAR-T cells targeting proteins like CD70, CD47, and PDL-1, which can effectively reduce tumor cells by overcoming inhibitory signaling pathways, suggesting a potential for improved cancer treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cells Targeting Immune Checkpoint Pathway Players. Golubovskaya, V.[2022]

CAR-T cell therapy has shown significant success in treating CD19-positive B-cell cancers, but this review explores its potential in other blood cancers, particularly Hodgkin's lymphoma and acute myeloid leukemia.

The focus on hematologic malignancies beyond CD19 highlights the expanding applications of CAR-T cell technology, suggesting it may be effective for a broader range of blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cells beyond CD19, UnCAR-Ted territory. Leick, MB., Maus, MV.[2020]

References

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

Significantly increased anti-tumor activity of carcinoembryonic antigen-specific chimeric antigen receptor T cells in combination with recombinant human IL-12. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. [2023]

4. England pubmed.ncbi.nlm.nih.gov

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

5. Switzerland pubmed.ncbi.nlm.nih.gov

Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents. [2023]

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

Driving better and safer HER2-specific CARs for cancer therapy. [2019]

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

Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Cancer CARtography: charting out a new approach to cancer immunotherapy. [2021]

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

From bench to bedside: the history and progress of CAR T cell therapy. [2023]

10. Singapore pubmed.ncbi.nlm.nih.gov

CAR-T Cells Targeting Immune Checkpoint Pathway Players. [2022]

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

CAR-T cells beyond CD19, UnCAR-Ted territory. [2020]