CAR T-cell Therapy for Blood Cancers

Overseen By Swati Naik, MBBS

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Primary immunodeficiency, HIV, Severe infection, APL, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

24 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, since the trial involves chemotherapy, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.

What data supports the effectiveness of the treatment CD70-CAR T cell infusion for blood cancers?

Research shows that T cells modified to target CD70 can effectively recognize and kill cancer cells expressing CD70, leading to tumor regression in animal models. This suggests that CD70-CAR T cells could be a promising treatment for certain blood cancers. ^{1 2 3 4 5}

Is CAR T-cell therapy generally safe for humans?

CAR T-cell therapy has shown to be generally safe for most patients, but it can cause side effects like cytokine release syndrome (a severe immune reaction), neurologic toxicity, and targeting of healthy tissues. Researchers are working on ways to reduce these risks and improve safety. ^{1 6 7 8 9}

How is CD70-CAR T-cell therapy different from other treatments for blood cancers?

CD70-CAR T-cell therapy is unique because it involves genetically modifying a patient's own T-cells to specifically target the CD70 protein on cancer cells, which is different from other CAR T-cell therapies that target different proteins like CD19. This personalized approach harnesses the patient's immune system to fight cancer, offering a novel mechanism of action compared to traditional chemotherapy or radiation. ^{1 2 10 11 12}

What is the purpose of this trial?

The study participant has one of the following blood cancers: acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (B-ALL, T-ALL) or Lymphoma. Your cancer has been difficult to treat (refractory) or has come back after treatment (relapse). Primary Objective To determine the safety and maximum tolerated dose of intravenous infusions of escalating doses of CD70-CAR T cells in patients (≤21 years) with recurrent/refractory CD70+ hematological malignancies after lymphodepleting chemotherapy. Secondary Objectives To evaluate the antileukemic activity of CD70-CAR T cells. We will determine the anti- leukemic activity of the CD70-CAR T cells in the bone marrow and in the treatment of extramedullary disease.

Research Team

Swati Naik, MBBS

Principal Investigator

St. Jude

Eligibility Criteria

This trial is for children and young adults (21 years old or younger) with certain blood cancers that are hard to treat or have returned after treatment. These include acute myeloid leukemia, myelodysplastic syndrome, lymphoma, and acute lymphoblastic leukemia.

Inclusion Criteria

Estimated life expectancy of >12 weeks

My cancer did not respond to the first 3 rounds of chemotherapy.

For females of childbearing age: i. Not lactating with intent to breastfeed, ii. Not pregnant with negative serum or urine pregnancy test within 7 days prior to enrollment

Exclusion Criteria

I cannot take Fludarabine/cyclophosphamide due to health reasons.

Known primary immunodeficiency

Known history of HIV positivity

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive a lymphodepleting chemotherapy regimen (fludarabine and cyclophosphamide) to prepare for CAR T-cell infusion

1 week

Treatment

Participants receive a single autologous infusion of CD70-CAR T cells

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CD70-CAR T cell infusion

Trial Overview The trial tests a new therapy where patients receive special immune cells called CD70-CAR T cells designed to target their cancer. Before these cells are given, patients get chemotherapy drugs (Cyclophosphamide and Fludarabine) to prepare their bodies.

Participant Groups

Group I: CD70- CAR T cell Therapy Experimental Treatment 4 Interventions

Patients will receive autologous (their own) cells.

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

CAR T cell therapy has become an important treatment for certain blood cancers, with three types of anti-CD19 CAR-T cells already approved for use in the Czech Republic, and more trials underway for targeting other cancer-specific antigens.

While the management of CAR-T cell therapy has improved, including updated guidelines for early toxicity, long-term follow-up is essential due to potential late toxicities, highlighting the need for ongoing research to enhance efficacy and reduce side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical aspects of CAR-T cell therapy. Jana, M., Tomáš, J., Michal, K., et al.[2022]

CAR T-cell therapy is a personalized treatment for blood cancers, showing remarkable success in managing B-cell malignancies like lymphoblastic leukemia and non-Hodgkin lymphoma since its clinical introduction in 2017.

The therapy works by genetically modifying a patient's own T-cells to target specific tumor antigens, such as CD19, enhancing the immune response against cancer cells, but emphasizes the need for standardization and quality control to ensure safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cells: Properties, production, and quality control. Ramesh, P., Hui, HYL., Brownrigg, LM., et al.[2023]

CAR T-cell therapy, particularly targeting CD19, has shown remarkable efficacy with approximately 90% complete response rates in patients with relapsed or refractory acute lymphoblastic leukemia, demonstrating its potential as a powerful treatment for B-cell malignancies.

Ongoing research is focused on enhancing the safety and effectiveness of CAR T cells, including exploring their use in solid tumors and in combination with other therapies, indicating a promising future for this innovative cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. Maus, MV., June, CH.[2023]

Genetically modified T cells targeting CD70 show promise for treating a wide range of hematologic malignancies and some solid tumors, expanding the potential of T-cell therapies beyond B cell-derived cancers.

The study demonstrated that CD70-specific T cells can effectively recognize and kill tumor cells, leading to sustained regression of tumors in mouse models, indicating their potential as a new immunotherapy option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Shaffer, DR., Savoldo, B., Yi, Z., et al.[2021]

CAR T cell therapy has revolutionized the treatment of blood cancers like leukemia and lymphoma, but its effectiveness in solid tumors has been significantly lower due to various challenges.

Key obstacles for CAR T cell therapy in solid tumors include the lack of unique tumor antigens, difficulties in T cell movement to tumor sites, tumor diversity, and a highly immunosuppressive environment, prompting ongoing research to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions. Bagley, SJ., O'Rourke, DM.[2020]

Chimeric antigen receptor (CAR) T-cell therapy has shown promising results in prolonging survival for patients with relapsed or refractory B-cell malignancies, as evidenced by numerous clinical trials targeting CD19 and CD20.

While CAR T-cell therapy is generally safe and well-tolerated, potential safety concerns include insertional mutagenesis, off-target effects, and inflammatory responses, which need to be carefully monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Advances in immunotherapy of hematological malignancies by using chimeric antigen receptor-modified lymphocytes]. Xu, XJ., Zhao, HZ., Tang, YM.[2018]

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 cell therapy has shown great promise in treating certain blood cancers, but it can lead to serious side effects, including potentially fatal toxicities from cytokine release and off-target effects that harm healthy tissues.

Recent strategies to improve safety include modifying CAR structures and incorporating elements like switch molecules and suicide genes to reduce the toxic effects of CAR T cells on normal tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for modifying the chimeric antigen receptor (CAR) to improve safety and reduce toxicity in CAR T cell therapy for cancer. Sayadmanesh, A., Yekehfallah, V., Valizadeh, A., et al.[2023]

CAR-T cell therapy shows significant efficacy in treating hematological malignancies, but it is associated with high rates of hematological toxicity, with 80% of patients experiencing any grade of neutropenia, 61% thrombocytopenia, and 68% anemia based on a meta-analysis of 52 studies involving 2004 patients.

Severe hematological toxicities (grade ≥3) were notably high, with 60% experiencing neutropenia, 33% thrombocytopenia, and 32% anemia, particularly in younger patients and those with a history of multiple prior therapies, highlighting the need for careful monitoring and intervention to prevent life-threatening complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis. Luo, W., Li, C., Zhang, Y., et al.[2022]

CAR-T cell therapy is a highly effective and individualized treatment for hematologic malignancies, showing impressive antitumor efficacy and long-lasting remissions in patients with conditions like diffuse large B cell lymphoma and acute lymphoblastic leukemia after just one infusion.

The process of producing CAR-T cells is safe and well-tolerated in both children and adults, and ongoing improvements aim to enhance T cell persistence while reducing side effects such as cytokine release syndrome and neurotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leukapheresis for CAR-T cell production and therapy. Pessach, I., Nagler, A.[2023]

CAR-T cell therapy has shown great promise in treating blood cancers and may also be expanded to treat solid tumors, indicating its potential as a major treatment option in oncology.

The review discusses the engineering process of CAR-T cells, including patient cell harvesting and processing, while also highlighting the associated toxicities and clinical effectiveness observed in patients with advanced cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapies From the Transfusion Medicine Perspective. Fesnak, A., Lin, C., Siegel, DL., 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. Czech Republic pubmed.ncbi.nlm.nih.gov

Practical aspects of CAR-T cell therapy. [2022]

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

Chimeric antigen receptor T-cells: Properties, production, and quality control. [2023]

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

Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. [2023]

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

T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions. [2020]

6. China pubmed.ncbi.nlm.nih.gov

[Advances in immunotherapy of hematological malignancies by using chimeric antigen receptor-modified lymphocytes]. [2018]

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

Toxicity and management in CAR T-cell therapy. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Strategies for modifying the chimeric antigen receptor (CAR) to improve safety and reduce toxicity in CAR T cell therapy for cancer. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Leukapheresis for CAR-T cell production and therapy. [2023]

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

CAR-T Cell Therapies From the Transfusion Medicine Perspective. [2018]

12. 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]