WU-CART-007 for T-Cell Leukemia
Recruiting in Palo Alto (17 mi)
+7 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Wugen, Inc.
Must not be taking: Steroids, Anti-neoplastic agents
Disqualifiers: HIV, Active hepatitis, CNS leukemia, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?The main purpose of this study is to evaluate the Composite Complete Remission Rate (CRc) of WU-CART-007 in Relapsed/Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL)/Lymphoblastic Lymphoma (LBL) patients and to evaluate the efficacy of WU-CART-007 to induce complete Minimum Residual Disease (MRD) negative response
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications, but it does mention that certain medications, like steroids or anti-cancer drugs, are not allowed. It's best to discuss your current medications with the trial team to see if any changes are needed.
What data supports the effectiveness of the treatment WU-CART-007 for T-Cell Leukemia?
Research shows that targeting CD7, a common marker on T-cell leukemia cells, with CAR T-cell therapy has led to remission in patients with difficult-to-treat T-cell leukemia. In one study, a similar CD7-targeted treatment led to complete response in 11 out of 12 patients, showing promising results for this approach.
12345What safety data exists for WU-CART-007 or similar treatments for T-cell leukemia?
Research shows that CD7-targeted CAR T-cell therapies, like WU-CART-007, have been generally safe in humans, with some patients experiencing mild to moderate side effects such as cytokine release syndrome (a condition where the immune system is overly activated) and neurotoxicity (nervous system side effects). These side effects were mostly reversible and manageable.
15678How is the WU-CART-007 treatment different from other treatments for T-cell leukemia?
WU-CART-007 is a unique treatment for T-cell leukemia because it uses genetically modified T-cells to specifically target and attack cancer cells expressing the CD7 protein, which is common in T-cell malignancies. This approach is different from traditional therapies as it involves engineering the patient's own immune cells to fight the cancer, potentially offering a more targeted and effective treatment option.
13567Eligibility Criteria
This trial is for people with T-Cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma that didn't respond to initial treatment, relapsed within 24 months of diagnosis, failed re-induction therapy after recurrence, or have persistent disease after a stem cell transplant. Participants need normal liver and kidney function and adequate respiratory capacity.Inclusion Criteria
My liver enzyme levels are not more than 5 times the normal limit.
My bilirubin levels are within the normal range, or slightly above if I have Gilbert's Syndrome.
My oxygen levels stay above 91% without extra oxygen.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Lymphodepletion Therapy
Participants undergo lymphodepletion therapy prior to receiving the CAR-T cell infusion
1 week
Treatment
A single IV infusion of WU-CART-007 Cells on Day 1 after Lymphodepletion Therapy
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
24 months
Participant Groups
The study tests WU-CART-007, an experimental CAR-T cell therapy targeting CD7 in patients with relapsed/refractory T-cell leukemia/lymphoma. It aims to see if the treatment can achieve complete remission and eliminate minimal residual disease.
1Treatment groups
Experimental Treatment
Group I: WU-CART-007Experimental Treatment1 Intervention
A CD7-directed chimeric antigen receptor (CAR) T-cell product.
A single IV infusion of WU-CART-007 Cells on Day 1 after Lymphodepletion(LD) Therapy.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of HopeDuarte, CA
Children's Hospital Los AngelesLos Angeles, CA
Moffit Cancer CenterTampa, FL
Washington University Saint LouisSaint Louis, MO
More Trial Locations
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Who Is Running the Clinical Trial?
Wugen, Inc.Lead Sponsor
References
Engineering naturally occurring CD7- T cells for the immunotherapy of hematological malignancies. [2023]Chimeric antigen receptor (CAR) T-cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7- T cells to generate CD7-CAR (CD7-CARCD7-) T cells. CD7-CARCD7- T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7- T cells for the immunotherapy of CD19+ hematological malignancies. Direct comparison of nonselected (bulk) CD19-CAR and CD19-CARCD7- T cells revealed that CD19-CARCD7- T cells had enhanced antitumor activity compared with their bulk counterparts in vitro and in vivo. Lastly, to gain insight into the behavior of CD19-CAR T cells with low levels of CD7 gene expression (CD7lo) in humans, we mined single-cell gene and T-cell receptor (TCR) expression data sets from our institutional CD19-CAR T-cell clinical study. CD19-CARCD7lo T cells were present in the initial CD19-CAR T-cell product and could be detected postinfusion. Intriguingly, the only functional CD4+ CD19-CAR T-cell cluster observed postinfusion exhibited CD7lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7lo T cells than nonresponders (NCT03573700). Thus, CARCD7- T cells have favorable biological characteristics and may present a promising T-cell subset for adoptive cell therapy of T-ALL and other hematological malignancies.
Chimeric antigen receptor T cells (CAR-T) for the treatment of T-cell malignancies. [2020]At present, the only curative therapy for patients with T-cell malignancies is allogeneic stem cell transplant, which has associated risks and toxicities. Novel agents have been tried in relapsed T-cell acute lymphoblastic leukemia (T-ALL), but only one, with 20%-30% complete remission rates, has been approved by the US Food and Drug Administration. T-ALL is a heterogeneous disease, but it has universal overexpression of CD7 as well as several other T-cell markers, such as CD2 and CD5. T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown great potential for inducing both remissions and even long-term relapse-free survival in patients with B-cell leukemia and lymphoma. UCART7 for CD7+ T-cell malignancies is in development for treatment of relapsed T-ALL in children and adults. It may also have potential in other CD7+ hematologic malignancies that lack both effective therapies and targeted therapies. The challenges encountered and progress made in developing a novel fratricide-resistant "off-the-shelf" CAR-T (or UCART7) that targets CD7+ T-cell malignancies are discussed here.
CD7 targeted "off-the-shelf" CAR-T demonstrates robust in vivo expansion and high efficacy in the treatment of patients with relapsed and refractory T cell malignancies. [2023]T-cell acute lymphoblastic leukemia (T-ALL) represents an area of highly unmet medical needs. Once relapsed, patients have limited treatment options and poor prognosis. T-ALL antigens such as CD7 is extensively expressed in normal T cells and natural killer (NK) cells, and extending the success of CAR-T therapy to T cell malignancies was challenged by CAR-T cell fratricide, high production cost, and potential product contaminations. GC027 is an "off-the-shelf" allogeneic CD7 targeted CAR-T therapeutic product for T cell malignancies. It demonstrated superior cell expansion and antileukemia efficacy in mouse xenograft model. In our previous study, we observed promising efficacy results in the first two relapsed and refractory(R/R) T-ALL patients treated with GC027. In the expanded study, 11 out of 12 patients had rapid eradication of T-lymphoblasts and reached complete response within 1-month after GC027 infusion. GC027 cells expanded quickly beginning at infusion and reached to peak around 5-10 days after infusion. For most patients with a response(9/11), GC027 could not be detected via flow cytometry or qPCR 4 weeks after infusion. One patient had progression free survival of >3 years. With manageable toxicity profile, GC027 demonstrated superior clinical efficacy to standard chemotherapy regimens in (R/R) T cell malignancies.
Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies. [2022]Effective immunotherapies for T-cell malignancies are lacking. We devised a novel approach based on chimeric antigen receptor (CAR)-redirected T lymphocytes. We selected CD7 as a target because of its consistent expression in T-cell acute lymphoblastic leukemia (T-ALL), including the most aggressive subtype, early T-cell precursor (ETP)-ALL. In 49 diagnostic T-ALL samples (including 14 ETP-ALL samples), median CD7 expression was >99%; CD7 expression remained high at relapse (n = 14), and during chemotherapy (n = 54). We targeted CD7 with a second-generation CAR (anti-CD7-41BB-CD3ζ), but CAR expression in T lymphocytes caused fratricide due to the presence of CD7 in the T cells themselves. To downregulate CD7 and control fratricide, we applied a new method (protein expression blocker [PEBL]), based on an anti-CD7 single-chain variable fragment coupled with an intracellular retention domain. Transduction of anti-CD7 PEBL resulted in virtually instantaneous abrogation of surface CD7 expression in all transduced T cells; 2.0% ± 1.7% were CD7+ vs 98.1% ± 1.5% of mock-transduced T cells (n = 5; P < .0001). PEBL expression did not impair T-cell proliferation, interferon-γ and tumor necrosis factor-α secretion, or cytotoxicity, and eliminated CAR-mediated fratricide. PEBL-CAR T cells were highly cytotoxic against CD7+ leukemic cells in vitro and were consistently more potent than CD7+ T cells spared by fratricide. They also showed strong anti-leukemic activity in cell line- and patient-derived T-ALL xenografts. The strategy described in this study fits well with existing clinical-grade cell manufacturing processes and can be rapidly implemented for the treatment of patients with high-risk T-cell malignancies.
Haploidentical CD7 CAR T-cells induced remission in a patient with TP53 mutated relapsed and refractory early T-cell precursor lymphoblastic leukemia/lymphoma. [2022]Patients with relapsed/refractory early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) respond poorly to traditional therapy and have dismal prognosis. CD7 is a promising therapeutic targets for chimeric antigen receptor modified T cell therapy (CART) due to its widely expression in almost all T-cell malignancies. Here we present the anti-CD7 CART therapy in a 11-year-old male with TP53 mutated relapsed/refractory ETP-ALL/LBL. The patient suffered second relapse after haploidentical hematopoietic stem cell transplantation, showing resistance to 4 lines salvage therapies including venetoclax. Nanobody derived CD7-CART cells were manufactured by co-transducing CAR-T cells with a CD7 protein expression blocker. 70.5% of blasts (CD7 expression: 92.6%) and extensive extramedullary disease (mediastinal mass, enlarged lymph nodes and spleen) were observed prior to CD7-CART-cell therapy. A total of 5 × 106/kg donor-derived CD7-CART-cells were infused. Hematological and extramedullary remission were both achieved, with persistence of CD7-CART-cells be detected until the last followup at 96th days after the infusion. Reversible adverse effects including grade 3 cytokine release syndrome and macrophage activation syndrome were observed. This case demonstrated that CD7-CART was a potent and safe salvage therapy in relapsed/refractory ETP-ALL/LBL patient with high tumor burden.Trial registration: ClinicalTrials. gov, NCT04785833 , Registered on March 8, 2021, prospectively registered.
Naturally selected CD7 CAR-T therapy without genetic manipulations for T-ALL/LBL: first-in-human phase 1 clinical trial. [2022]Derivation of CD7-targeted chimeric antigen receptor (7CAR) T cells often requires genetic manipulations to ablate the CD7 gene or block CD7 cell surface expression. Our novel approach deriving naturally selected 7CAR (NS7CAR) T cells from bulk T cells was able to overcome major fratricide by minimizing accessible CD7 epitopes. The CD7 molecules of NS7CAR T cells were masked or sequestered by the CD7-targeting CAR. Compared with sorted CD7-negative 7CAR T cells and CD7 knocked-out 7CAR T cells, NS7CAR exhibited similar or superior therapeutic properties, including a greater percentage of CAR+ cells and a higher proportion of CD8+ central memory T cells. In our first-in-human phase 1 trial (NCT04572308), 20 patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) (n = 14) and T-cell lymphoblastic lymphoma (T-LBL) (n = 6) were treated with NS7CAR. Nineteen patients achieved minimal residual disease negative complete remission (CR) in the bone marrow (BM) by day 28, and 5 of 9 patients achieved extramedullary CR. With a median follow-up of 142.5 (32-311) days after infusion, 14 patients subsequently received allogeneic hematopoietic stem cell transplant (10 consolidative, 4 salvage) following NS7CAR infusion with no relapses to date. Of the 6 patients who did not receive a transplant, 4 remained in CR at a median time of 54 (32-180) days. Eighteen patients experienced mild cytokine release syndrome (CRS) (grade ≤2), 1 developed grade 3 CRS, and 2 had grade 1 neurotoxicity. These results indicate that NS7CAR-T therapy is a safe and highly effective treatment for T-ALL/LBL. More patients and longer follow-up are needed for validation.
Eradication of T-ALL Cells by CD7-targeted Universal CAR-T Cells and Initial Test of Ruxolitinib-based CRS Management. [2022]Although chimeric antigen receptor T-cell (CAR-T) therapy development for B-cell malignancies has made significant progress in the last decade, broadening the success to treating T-cell acute lymphoblastic leukemia (T-ALL) has been limited. We conducted two clinical trials to verify the safety and efficacy of GC027, an "off-the-shelf" allogeneic CAR-T product targeting T-cell antigen, CD7. Here, we report 2 patients as case reports with relapsed/refractory T-ALL who were treated with GC027.
Chimeric Antigen Receptor T-cell Therapy: Current Status and Clinical Outcomes in Pediatric Hematologic Malignancies. [2022]Chimeric antigen receptor T-cell (CART) therapy has transformed the treatment paradigm for pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), with complete remission rates in key pivotal CD19-CART trials ranging from 65% to 90%. Alongside this new therapy, new toxicity profiles and treatment limitations have emerged, necessitating toxicity consensus grading systems, cooperative group trials, and novel management approaches. This review highlights the results of key clinical trials of CART for pediatric hematologic malignancies, discusses the most common toxicities seen to date, and elucidates challenges, opportunities, and areas of active research to optimize this therapy.