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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy called CD70-targeted CAR T-cell therapy for cancers that produce the CD70 protein. Researchers modify a person's white blood cells to attack cancer cells, aiming to shrink tumors safely. The study has two parts, each testing different doses and methods. People who have previously tried standard cancer treatments without success and whose cancer shows CD70 could be good candidates for this trial. Participants should manage hospital visits and follow post-treatment care instructions.

As a Phase 1 and Phase 2 trial, this study focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group. It offers participants a chance to be among the first to benefit from this innovative therapy.

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.

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

Research shows that anti-CD70 CAR T-cell therapy might help treat certain cancers. Early lab studies have shown it can shrink tumors. In tests with mice, these modified cells successfully targeted and attacked cancer cells.

Early human trials primarily focus on assessing the treatment's safety. Researchers closely monitor the treatment for any side effects. So far, participants have generally tolerated it well, although side effects can occur, as with any treatment. Participants in these studies have received supportive care, like antibiotics and other medications, to help manage any side effects.

Overall, while it's still early, evidence suggests this treatment is safe enough for further testing. Medical professionals will closely monitor anyone considering joining a trial throughout the process. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the CD70-targeted CAR T-cell therapy because it represents a novel approach to treating cancer by harnessing the power of the immune system. Unlike standard treatments like chemotherapy and radiation, which target cancer cells broadly, this therapy specifically targets the CD70 protein found on the surface of certain cancer cells, potentially minimizing damage to healthy cells. Additionally, the use of genetically modified peripheral blood lymphocytes (PBL) means the treatment is tailored to each patient, potentially leading to more effective and personalized outcomes. The therapy also includes a unique combination with high-dose aldesleukin, which may enhance the immune response against cancer cells.

What evidence suggests that this treatment might be an effective treatment for cancer?

Research has shown that using CAR T-cells to target CD70 can help shrink tumors. In lab studies, cells modified to attack CD70 were more effective at fighting cancer than regular cells. Animal studies demonstrated that these modified cells reduced tumor size and extended survival. CD70 is a protein that aids cancer growth and spread, so blocking it can weaken the cancer. Early results suggest that targeting CD70 is a promising approach for treating cancers with this protein. Participants in this trial will receive anti-hCD70 CAR transduced PBL therapy. Some will receive escalating doses, while others will receive the maximum tolerated dose, both combined with a non-myeloablative, lymphodepleting preparative regimen and high-dose aldesleukin. ^{1 2 3 5 6}

Who Is on the Research Team?

James C Yang, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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.

Your total bilirubin level is less than 2.0 mg/dL, unless you have Gilbert's Syndrome, in which case it should be less than 3.0 mg/dL.

Exclusion Criteria

I am currently on systemic steroid therapy.

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02830724

Study Details | NCT02830724 | Administering Peripheral ...

This is a phase I/II, single center study of PBL transduced with anti-hCD70 CAR in patients with measurable, unresectable cancer expressing CD70. PBMC obtained ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12522704/

CD70-targeted CAR-T/NK therapy - PubMed Central - NIH

According to Lin et al., in vitro experiments showed that transduced NK cells had a better outcome than untransduced NK cells. CD70-targeted CAR-NK had a ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5411349/

Pre-clinical Evaluation of Chimeric Antigen Receptors ...

In the murine CD27-CD3-zeta CAR model, significant reduction of established tumors and prolonged survival were achieved using CAR-transduced splenocytes in a ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S0304383524008231

A mechanistic, functional, and clinical perspective on ...

CD70 regulates tumor evasion, proliferation, invasion, metastasis, EMT, and stemness. Expression of CD70 correlates with tumor progression and mortality.

5.

cell.com

cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00660-8

CD70-targeted iPSC-derived CAR-NK cells display potent ...

CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells.

6.

sciencedirect.com

sciencedirect.com/science/article/pii/S0093775425001034

Rethinking CAR-T for pancreatic cancer

The primary objectives are to determine the safety of administering PBL transduced with anti-hCD70 CAR alongside lymphodepletion and high ...