Cellular Immunotherapy After Chemotherapy for Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Uncontrolled illness, Active infection, Active malignancy, others

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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for treating certain blood cancers, such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia, that have returned after treatment. It combines chemotherapy with a specialized cellular immunotherapy, using modified white blood cells (Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes) to help the immune system fight cancer. Researchers aim to determine the optimal dose and understand any side effects of this treatment. It suits individuals with these specific cancers who have experienced a recurrence after previous treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. You must be at least two weeks from your last dose of immunosuppressant medications and certain chemotherapy drugs. Oral chemotherapy drugs like lenalidomide and ibrutinib are allowed if enough time has passed since your last dose.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that autologous CD19CAR T-cell therapy, a type of cellular immunotherapy, has been studied for its safety in treating non-Hodgkin lymphoma. The findings suggest that this treatment is generally safe for patients with high-risk lymphoma. These studies have mainly focused on individuals who have undergone intense cancer treatments like stem cell transplants.

The treatment modifies a patient's own white blood cells to help the immune system fight cancer. Previous studies did not find any major safety issues, but mild to moderate side effects can occur. These might include fever, chills, or low blood pressure, which are common with this kind of therapy.

Since this trial is in the early phase, it primarily examines safety and dosage. This means there's still much to learn about how well people tolerate the treatment. The trial phase indicates that researchers are still gathering information on side effects and the optimal dosage. While the therapy is being tested for safety, potential participants should discuss any concerns with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing T-lymphocytes for treating Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL) because this treatment is a form of cellular immunotherapy. Unlike traditional chemotherapy that broadly attacks rapidly dividing cells, this therapy specifically targets cancer cells by using genetically modified T-cells. These T-cells are engineered to recognize and destroy cancer cells expressing the CD19 protein, offering a more precise attack on the disease. Additionally, this approach allows for potential re-treatment, where patients can receive a second infusion if needed, which may enhance long-term effectiveness and remission rates.

What evidence suggests that this trial's treatments could be effective for non-Hodgkin's lymphoma and chronic lymphocytic leukemia?

Research shows that a new treatment using a patient's own modified immune cells has potential in treating certain blood cancers. In this trial, participants will receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes, a form of cellular immunotherapy. Earlier studies demonstrated that these specially altered cells successfully targeted and destroyed cancer cells in patients with conditions like non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This treatment reprograms a patient's immune cells to better fight cancer. Initial results suggest that this method can significantly reduce cancer in some patients. While more research is needed, this treatment is seen as a promising option for cases where cancer has returned or is hard to treat. ^{4 5 6 7 8}

Who Is on the Research Team?

Tanya Siddiqi

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with certain types of blood cancers that have returned, including various non-Hodgkin lymphomas and chronic leukemias. Participants should have a life expectancy of at least 16 weeks, be able to use contraception, understand the study and consent to it, have adequate organ function (kidney, liver, heart), not be on immunosuppressants or other disqualifying treatments recently, and not need oxygen or intensive care support.

Inclusion Criteria

I have a specific type of lymphoma or leukemia and may not have qualified for certain other treatments.

I have CLL, PLL, or SLL.

I am able to care for myself but may not be able to do active work.

Exclusion Criteria

Participants who have previously received a specific type of experimental treatment.

I do not have any uncontrolled illnesses that would affect my study participation.

I do not have active hepatitis B or C, HIV, or any signs of active infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine phosphate, etoposide.

1 week

Cellular Immunotherapy

Patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15 minutes on day 0. Patients with relapsed, residual or progressive disease may receive an optional second infusion.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes every 2 days for 14 days, weekly for 1 month, monthly for 1 year, and then yearly for at least 15 years.

15 years

What Are the Treatments Tested in This Trial?

Interventions

• Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes
• Bendamustine Hydrochloride
• Cyclophosphamide
• Etoposide
• Fludarabine Phosphate

Trial Overview The trial tests a cellular immunotherapy where white blood cells are genetically modified to attack cancer following chemotherapy. It aims to determine the best dose and side effects of this treatment in patients whose disease has recurred after previous therapies.

How Is the Trial Designed?

Group I: Group II (lymphodepletion, cellular immunotherapy) Experimental Treatment 5 Interventions

LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine phosphate, etoposide. CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15 minutes on day 0. Patients with relapsed, residual or progressive disease may receive an optional second infusion of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes \>= 28 days post T cell infusion. Disease status: Patients with Chronic lymphocytic leukemia (CLL) and/or Prolymphocytic Leukemia (PLL).

Group II: Group I (lymphodepletion, cellular immunotherapy) Experimental Treatment 5 Interventions

LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine phosphate, etoposide. CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15 minutes on day 0. Patients with relapsed, residual or progressive disease may receive an optional second infusion of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes \>= 28 days post T cell infusion. Disease status: Patients with Non-Hodgkin lymphoma (NHL).

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of fludarabine and cyclophosphamide effectively reduces tumor burden in chronic lymphocytic leukemia, but it also leads to a significant reduction in CD4(+) and CD8(+) T cells, indicating potential immunosuppressive effects.

Despite the depletion of T cells, the surviving T cells exhibit a more mature phenotype and increased responsiveness to stimulation, suggesting that fludarabine/cyclophosphamide therapy may create a favorable environment for subsequent T cell activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. Gassner, FJ., Weiss, L., Geisberger, R., et al.[2021]

In a study involving 561 patients with chronic lymphocytic leukaemia, the standard treatment of fludarabine, cyclophosphamide, and rituximab showed a longer median progression-free survival of 55.2 months compared to 41.7 months for the bendamustine and rituximab combination, indicating that the standard therapy is more effective.

However, the bendamustine and rituximab combination was associated with significantly fewer severe side effects, such as neutropenia and infections, making it a potentially safer alternative for patients, especially those over 65 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Eichhorst, B., Fink, AM., Bahlo, J., et al.[2022]

The T(R)EC regimen, which replaces ifosfamide with bendamustine, demonstrated high response rates of 85% in classic Hodgkin lymphoma and 65% in diffuse large B cell lymphoma, indicating its efficacy as a treatment for relapsed or refractory cases.

This outpatient treatment was found to be safe, with no dose-limiting toxicities and successful stem cell collection in 30 out of 32 patients, making it a promising alternative to the traditional (R)ICE regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial. Budde, LE., Wu, D., Martin, DB., et al.[2022]

In a study of 34 patients with multiple myeloma, the combination of bendamustine, etoposide, and dexamethasone (BED) successfully mobilized hematopoietic stem cells in all participants, with a median yield of 21.60 million cells per kg of body weight.

The treatment was effective and safe, with 88% of patients needing only one apheresis session, although six patients experienced serious nonhematologic adverse events, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Green, DJ., Bensinger, WI., Holmberg, LA., et al.[2023]

The study evaluated an immunotherapy regimen combining rIL-2, rIFN-alpha, and histamine in a patient with relapsing aggressive non-Hodgkin's lymphoma, showing significant increases in T-cell responses and natural killer (NK) cell activity during chemotherapy-induced remission.

The treatment led to enhanced production of key cytokines (IFN-gamma, IL-4, and TNF-alpha) by T-cells, indicating a robust immune response, while also reducing potentially regulatory lymphocytes, suggesting a promising approach to boost immune function in lymphoma patients post-chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stimulation of T-cell cytokine production and NK-cell function by IL-2, IFN-alpha and histamine treatment during remission of non-Hodgkin's lymphoma. Ahlberg, R., MacNamara, B., Andersson, M., et al.[2016]

Fludarabine is currently the most effective treatment for chronic lymphocytic leukemia, helping to activate apoptosis in abnormal lymphocytes, but it does not cure the disease.

For hairy-cell leukemia, treatments like pentostatin and 2-chlorodeoxyadenosine lead to durable complete remissions in 65% to 85% of patients, showing promising efficacy with similar toxicity levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia and hairy-cell leukemia. Cheson, BD.[2007]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11539471/

Advances in CAR-T therapy for central nervous system tumors This review examined the research progress of chimeric antigen receptor T-cell therapy in gliomas, medulloblastomas, and lymphohematopoietic tumors of the ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6094824/

Autologous CD19-Targeted CAR T Cells in Patients with ... We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/cd19car-cd28-cd3zeta-egfrt-expressing-tn-mem-enriched-t-lymphocytes

Clinical Trials Using CD19CAR-CD28-CD3zeta-EGFRt- ... Review the clinical trials studying cd19car-cd28-cd3zeta-egfrt-expressing tn/mem-enriched t-lymphocytes on this list and use the filters to refine the ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01815749

Study Details | NCT01815749 | Genetically Modified T-cell ... This phase I trial studies the side effects and best dose of genetically modified T-cells following peripheral blood stem cell transplant in treating ...

5. ashpublications.org ashpublications.org/blood/article/127/24/2980/35453/Phase-1-studies-of-central-memory-derived-CD19-CAR

Phase 1 studies of central memory–derived CD19 CAR T–cell ... Key Points. TCM-derived CD19 CAR T–cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02153580

Study Details | NCT02153580 | Cellular Immunotherapy ... This phase I trial studies the side effects and best dose of cellular immunotherapy following chemotherapy in treating patients with non-Hodgkin lymphomas, ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40836026/

Safety and efficacy of autologous humanized CD19 CAR-T ... Limited research has evaluated humanized CD19-targeted CAR-T cells (hCART19) in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).

8. db.idrblab.net db.idrblab.net/ttd/data/target-car-t/details/t56365

Targeted Antigens of CAR-T Cell Therapy Information Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes, Drug Info, Phase 1/2, Non-hodgkin lymphoma, [47]. Autologous CD19-targeting CAR T cells ...