CD70-Targeted CAR T-cell Therapy for Cancer

Overseen By NCI SB Immunotherapy Recruitment Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Investigational agents

Disqualifiers: Pregnancy, Infections, Autoimmune, others

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

Compensation: Varies

Number of Visits: 2

Duration: 6 weeks

124 Participants Needed

Trial Summary

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

The trial protocol does not specify if you need to stop taking your current medications. However, you must have completed any prior systemic therapy before enrolling, and you cannot be on systemic steroid therapy or other investigational agents.

What data supports the effectiveness of the CD70-targeted CAR T-cell treatment for cancer?

Research shows that CD70-targeted CAR T-cells can effectively recognize and kill cancer cells that express CD70, leading to tumor regression in animal models. This suggests that the treatment could be promising for cancers with CD70 expression. ^{1 2 3 4 5}

Is CD70-targeted CAR T-cell therapy generally safe for humans?

CAR T-cell therapies, including those targeting CD70, can cause serious side effects like prolonged blood-related issues and damage to healthy tissues that share the target with cancer cells. These treatments may also lead to life-threatening reactions due to their strong immune response. ^{6 7 8 9 10}

What makes the CD70-targeted CAR T-cell treatment unique for cancer?

This treatment is unique because it uses genetically modified T cells to specifically target CD70, a protein found on certain cancer cells but not widely present on normal cells, potentially reducing side effects compared to other therapies that target more common proteins. ^{1 2 4 6 11}

What is the purpose of this trial?

Background: In a new cancer therapy, researchers take a person s blood, select a certain white blood cell to grow in the lab, and then change the genes of these cells using a virus. The cells are then given back to the person. This is called gene transfer. For this study, researchers will modify the person s white blood cells with anti-CD70. Objectives: To see if a gene transfer with anti-CD70 cells can safely shrink tumors and to be certain the treatment is safe. Eligibility: Adults age 18 and older diagnosed with cancer that has the CD70-expressing cancer. Design: Participants will be screened with medical history, physical exam, scans, and other tests. They may by admitted to the hospital. Leukapheresis will be performed. For this, blood is removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm. Eligible participants will have an intravenous catheter placed in their upper chest. Over several days, they will get chemotherapy drugs and the anti-CD70 cells. They will recover in the hospital. Participants will take an antibiotic for 6 months after treatment. They will repeat leukapheresis. Participants will visit the clinic every 1-3 months for the first year after treatment, every 6 months for the second year, and then as determined by their physician. Follow-up visits will take 1-2 days. At each visit, participants will have lab tests, imaging studies, and a physical exam. Throughout the study, blood will be taken and participants will have many tests to determine the size and extent of their tumor and the treatment s impact.

Research Team

James C Yang, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18-72 with CD70-expressing cancers like kidney, breast, or ovarian cancer who've tried at least one standard treatment without success. They must have a certain level of blood cells and organ function, not be pregnant or breastfeeding, HIV negative, and willing to use birth control.

Inclusion Criteria

I have up to 3 small, symptom-free brain tumors or have had brain surgery.

I am fully active or restricted in physically strenuous activity but can do light work.

You do not have hepatitis B or C. If you test positive for hepatitis C, you need to have another test to make sure the virus is not in your blood.

Exclusion Criteria

I am currently on systemic steroid therapy.

I have an autoimmune disease that needs treatment to suppress my immune system.

You've had a serious allergic reaction to cyclophosphamide, fludarabine, or aldesleukin in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine, followed by anti-hCD70 CAR transduced PBL and high-dose aldesleukin

6 weeks

Hospital stay for treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment, with evaluations approximately 6 weeks after treatment and regular follow-up visits

12 weeks

Clinic visits every 1-3 months for the first year, then every 6 months for the second year

Long-term follow-up

Participants continue to be monitored for long-term safety and effectiveness, with visits as determined by their physician

Up to 2 years

Treatment Details

Interventions

• Anti-hCD70 CAR transduced PBL

Trial Overview The trial tests gene transfer therapy using modified white blood cells targeting CD70 on cancer cells. It includes chemotherapy drugs (cyclophosphamide and fludarabine) and aldesleukin before infusing the engineered cells. Participants will be monitored regularly for tumor response and safety.

Participant Groups

Group I: 2/Phase II Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-hCD70 CAR transduced PBL + high-dose aldesleukin

Group II: 1/Phase I Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-hCD70 CAR transduced PBL + high-dose aldesleukin

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 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]

Chimeric PD1 (chPD1) T-cells effectively target and kill a variety of solid tumors, including melanoma, pancreatic, and breast cancer, by recognizing PD1 ligands present on their surface, demonstrating their potential as a novel cancer therapy.

Although chPD1 T-cells did not survive beyond 14 days in the body, they successfully induced long-term anti-tumor memory responses, suggesting that they could provide lasting protection against cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cells expressing a chimeric-PD1-Dap10-CD3zeta receptor reduce tumour burden in multiple murine syngeneic models of solid cancer. Parriott, G., Deal, K., Crean, S., et al.[2021]

The study demonstrated that a CAR (chimeric antigen receptor) targeting CD70, specifically the trCD27-41BB-zeta variant, effectively produced high levels of IFNγ and could cure established CD70-expressing tumors in a mouse model, indicating strong potential efficacy for treating cancer.

While the treatment showed promise, preirradiation improved efficacy but also led to increased side effects like weight loss and hematopoietic suppression, highlighting the need to balance treatment effectiveness with safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers. Wang, QJ., Yu, Z., Hanada, KI., et al.[2019]

A novel CAR T-cell therapy targeting CD79b has been developed, showing strong antitumor activity against B-cell lymphomas in both laboratory and animal models, including the ability to attack tumors that have relapsed after CD19-targeted therapies.

The CD79b CAR T cells demonstrated effective proliferation and cytotoxic activity without significant signs of exhaustion, supporting their potential for use in a phase 1 clinical trial for patients with relapsed or refractory B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cells to target CD79b in B-cell lymphomas. Chu, F., Cao, J., Liu, J., et al.[2023]

In a mouse model with human Her2 expression, both high-affinity and low-affinity chimeric antigen receptor T cells (CARTs) caused liver damage, but low-affinity CARTs resulted in less toxicity and lower systemic inflammation compared to high-affinity CARTs.

Surprisingly, low-affinity CARTs showed better antitumor efficacy against Her2-positive tumors, likely due to their ability to migrate out of the liver and infiltrate tumors more effectively than high-affinity CARTs, suggesting that tuning T cell affinity can enhance safety and effectiveness in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A rational mouse model to detect on-target, off-tumor CAR T cell toxicity. Castellarin, M., Sands, C., Da, T., et al.[2021]

CAR T cell therapy targeting CD19 can effectively treat B cell malignancies but poses safety risks by also destroying healthy B cells that express the same antigen, leading to potential long-term tissue damage.

Research suggests that targeting activation-associated antigens, which are only temporarily present on stem cells, is safer than targeting lineage-associated antigens, which can harm tissue stem cells during their maturation process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shared target antigens on cancer cells and tissue stem cells: go or no-go for CAR T cells? Hombach, AA., Abken, H.[2017]

In a study of 31 adult patients with relapsed/refractory diffuse large B-cell lymphoma who received CAR T-cell therapy, 58% experienced prolonged hematologic toxicity (PHT), which significantly impacted their overall survival rates (36% vs. 81% at one year).

Several risk factors for PHT were identified, including the presence of cytokine release syndrome (CRS), use of tocilizumab or steroids, and elevated levels of ferritin and C-reactive protein, indicating the need for careful monitoring and management strategies in patients undergoing CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged hematologic toxicity following treatment with chimeric antigen receptor T cells in patients with hematologic malignancies. Nagle, SJ., Murphree, C., Raess, PW., et al.[2021]

Chimeric antigen receptor (CAR)-transduced T cells targeting CD30 have shown to be safe and effective in treating Hodgkin lymphoma (HL).

The review also highlights the challenges and ongoing trials of using CAR-T cells targeting CD5 and CD7 in T-cell lymphomas (TCL), indicating a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells in Hodgkin and T-Cell Lymphomas. Muhsen, IN., Hill, LC., Ramos, CA.[2023]

CAR-T cell therapy has shown strong effectiveness in treating B cell cancers, but its use in other types of cancers is limited due to serious side effects, including toxicities that affect normal tissues and severe cytokine-release syndromes.

The paper discusses potential strategies to reduce these toxicities and highlights the importance of preclinical animal models in predicting how well CAR-T cell therapy will work in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenges to chimeric antigen receptor (CAR)-T cell therapy for cancer. Magee, MS., Snook, AE.[2014]

The study developed a humanized anti-CD72 nanobody (H24) for CAR-T cell therapy, showing enhanced potency against B-cell tumors, including those that relapsed after CD19 CAR-T treatment, based on preclinical models.

H24 demonstrated no off-target binding and was identified as a promising clinical candidate, suggesting that modifications to the nanobody framework can improve therapeutic efficacy without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies. Temple, WC., Nix, MA., Naik, A., et al.[2023]

References

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

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

2. Singapore pubmed.ncbi.nlm.nih.gov

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

3. England pubmed.ncbi.nlm.nih.gov

T-cells expressing a chimeric-PD1-Dap10-CD3zeta receptor reduce tumour burden in multiple murine syngeneic models of solid cancer. [2021]

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

Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers. [2019]

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

Chimeric antigen receptor T cells to target CD79b in B-cell lymphomas. [2023]

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

A rational mouse model to detect on-target, off-tumor CAR T cell toxicity. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Shared target antigens on cancer cells and tissue stem cells: go or no-go for CAR T cells? [2017]

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

Prolonged hematologic toxicity following treatment with chimeric antigen receptor T cells in patients with hematologic malignancies. [2021]

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

Chimeric Antigen Receptor T Cells in Hodgkin and T-Cell Lymphomas. [2023]

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

Challenges to chimeric antigen receptor (CAR)-T cell therapy for cancer. [2014]

11. England pubmed.ncbi.nlm.nih.gov

Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies. [2023]