C-CAR168 CAR T Cell Therapy for Autoimmune Diseases

Overseen By Christine Cornwell

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AbelZeta Inc.

Must not be taking: Live vaccines, Rituximab

Disqualifiers: Hepatitis, HIV, Organ transplant, others

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

Compensation: Varies

Number of Visits: 4

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This multi-center, open-label, Phase 1/2 study aims to evaluate the safety, tolerability, and preliminary efficacy of C-CAR168, an autologous anti-CD20/BCMA CAR-T therapy, in patients with autoimmune diseases refractory to standard treatments. The study includes both dose escalation and dose expansion phases, with participants grouped into condition-specific cohorts. The purpose of this study is to: 1. Test the safety and ability for subjects with autoimmune refractory to standard treatment to tolerate the C-CAR168. 2. Determine the recommended Phase 2 dose of C-CAR168 in subjects with autoimmune disease refractory to standard treatment. Participants will be asked to: * Undergo screening to determine eligibility based on entry criteria. * Taper steroid use before leukapheresis. * Undergo leukapheresis for the manufacturing of C-CAR168. * Temporarily discontinue immunosuppressive therapy at least 7 days prior to leukapheresis. * Receive bridging therapy (steroids) if necessary to maintain disease stability during C-CAR168 manufacturing. * Undergo lymphodepletion therapy with fludarabine and cyclophosphamide. * Receive a single intravenous infusion of C-CAR168 at the assigned dose level on Day 0. * Attend regular safety and efficacy assessments for up to 24 months post-infusion. * Undergo dose-limiting toxicity evaluation during the first 28 days post-infusion (for those in the dose escalation phase). * Follow withdrawal procedures if necessary, including a discharge visit within 14 days if their condition deteriorates, unacceptable toxicity occurs, they no longer meet criteria, or they choose to withdraw.

Will I have to stop taking my current medications?

You will need to temporarily stop taking immunosuppressive medications at least 7 days before a procedure called leukapheresis. Additionally, you may need to taper off steroids before this procedure.

What data supports the effectiveness of the C-CAR168 treatment for autoimmune diseases?

Research shows that CAR T-cell therapy, like C-CAR168, has been successful in treating cancer and is now being explored for autoimmune diseases. Early studies suggest it can target and reduce harmful immune responses, potentially offering a more precise and lasting treatment for autoimmune conditions. ^{1 2 3 4 5}

What safety data exists for C-CAR168 CAR T Cell Therapy?

CAR T cell therapy, including C-CAR168, can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurological issues. These side effects are more common in patients with a high tumor burden before treatment. Other rare but serious risks include blood-related problems like hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation, which can be fatal. ^{6 7 8 9 10}

How is the C-CAR168 treatment different from other treatments for autoimmune diseases?

C-CAR168 is a unique treatment because it uses engineered T cells with chimeric antigen receptors (CARs) to specifically target and eliminate the immune cells causing the autoimmune response, offering a more precise and potentially curative approach compared to traditional broad immunosuppressive therapies. ^{1 3 5 11 12}

Research Team

Scott Antonia

Principal Investigator

Duke University

Eligibility Criteria

This trial is for patients with autoimmune diseases like Purpura Nephritis and Lupus, who haven't responded to standard treatments. They must be able to taper off steroids before leukapheresis, stop immunosuppressants before the procedure, and possibly receive steroids again if needed.

Inclusion Criteria

No active infection within 2 weeks before leukapheresis

Voluntary signed informed consent required

Life Expectancy greater than 6 months

Exclusion Criteria

Positive for Hepatitis B surface antigen (HBsAg)/core antibody (HBcAb)/e antibody (HBeAb)/e antigen (HBeAg), Hepatitis C Virus (HCV) antibodies, Human Immunodeficiency Virus (HIV) antibodies, or syphilis antigen or antibody

Received Prednisone treatment of ≥ 100 mg/d or equivalent corticosteroid therapy for ≥14 days within the previous 8 weeks; plasma exchange, plasma separation, hemodialysis, or IVIG within 14 days prior to leukapheresis; other investigational clinical study drug within 28 days prior to leukapheresis; CAR-T cell products or other genetically modified T cell therapies; Rituximab/ocrelizumab/obinutuzumab within 6 months prior to screening

Pregnant or breastfeeding women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis and Bridging Therapy

Participants taper steroid use, undergo leukapheresis for C-CAR168 manufacturing, and may receive bridging therapy to maintain disease stability.

3-4 weeks

2 visits (in-person)

Lymphodepletion and Treatment

Participants undergo lymphodepletion therapy followed by a single intravenous infusion of C-CAR168.

1 week

1 visit (in-person)

Dose Limiting Toxicity Evaluation

Participants are monitored for dose-limiting toxicities during the first 28 days post-infusion.

4 weeks

Weekly visits (in-person)

Follow-up

Participants attend regular safety and efficacy assessments for up to 24 months post-infusion.

24 months

Regular visits (in-person and virtual)

Treatment Details

Interventions

• C-CAR168

Trial Overview The study tests C-CAR168 CAR T Cell Therapy's safety and tolerability in a Phase 1/2 trial. It involves dose finding and expansion phases for those with refractory autoimmune diseases, including lymphodepletion therapy followed by a single infusion of C-CAR168.

Participant Groups

Group I: Arm 5: Dose Expansion Cohort Experimental Treatment 1 Intervention

Dose: To be selected based on MTD/RD identified in escalation phase. 12-24 additional subjects will be treated at the selected dose level. No staggered dosing required.

Group II: Arm 4: Dose Level 3 (DL3) Experimental Treatment 1 Intervention

Dose: 2.0 × 10⁶ CAR+ cells/kg Optional dose level pending SRC review and approval.

Group III: Arm 3: Dose Level 2 (DL2) Experimental Treatment 1 Intervention

Dose: 1.5 × 10⁶ CAR+ cells/kg Second dose level in escalation phase. Subject enrollment staggered by 28 days.

Group IV: Arm 2: Dose Level 1 (DL1) Experimental Treatment 1 Intervention

Dose: 0.75 × 10⁶ CAR+ cells/kg Starting dose for escalation phase. First 3 subjects must be staggered by 28 days.

Group V: Arm 1: Dose Level -1 (DL-1) Experimental Treatment 1 Intervention

0.5 × 10⁶ CAR+ cells/kg Optional dose level, administered only upon Safety Review Committee (SRC) recommendation.

Who Is Running the Clinical Trial?

AbelZeta Inc.

Lead Sponsor

AbelZeta, Inc.

Lead Sponsor

Trials

1

Recruited

20+

Findings from Research

Adoptive transfer of engineered T cells, specifically CAR T cells, shows promise as a potential curative therapy for autoimmune disorders, with early clinical results indicating effectiveness in conditions like systemic lupus erythematosus and myasthenia gravis.

Innovative approaches, such as chimeric autoantibody receptor T cells, are being developed to target specific B cell clones responsible for autoantibody production, while regulatory CAR T cells aim to modulate rather than eliminate autoreactive immune cells, highlighting a nuanced strategy in treating autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cells for treating autoimmune diseases. Blache, U., Tretbar, S., Koehl, U., et al.[2023]

Chimeric antigen receptor (CAR)-based therapies, originally developed for cancer treatment, are showing promise in treating autoimmune diseases by using CAR-T cells to target and deplete harmful immune cells, leading to favorable outcomes.

CAR-T regulatory T cells (Tregs) have potential in restoring immune tolerance in autoimmune diseases, and advancements in gene editing and synthetic biology are enhancing the effectiveness and safety of these CAR-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CARs: a new approach for the treatment of autoimmune diseases. Sun, Y., Yuan, Y., Zhang, B., et al.[2023]

CAR T cell therapy, particularly with the approval of tisagenlecleucel, has shown remarkable efficacy in treating pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia, with six therapies approved as of April 2023 for B-cell malignancies and multiple myeloma.

However, the therapy is associated with significant adverse events like cytokine release syndrome, which are more severe with higher pretreatment tumor burdens; thus, initiating therapy early or using a debulking strategy may help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From bench to bedside: the history and progress of CAR T cell therapy. Mitra, A., Barua, A., Huang, L., et al.[2023]

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

CAR T-cell therapy can lead to significant toxicities, particularly cytokine release syndrome (CRS) and neurologic toxicities, which require careful monitoring and management.

Recent guidelines and evidence-based practices are evolving to help healthcare professionals, especially nurses, effectively assess and manage these toxicities to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Associated Toxicities: Assessment and Management Related to CAR T-Cell Therapy. Anderson, K., Latchford, T.[2020]

A systematic analysis of CAR T-cell therapy adverse events revealed 5,112 reports of hematotoxicity, highlighting significant under-reporting of severe conditions like hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulation (DIC), which have high mortality rates of 69.9% and 59.6%, respectively.

The study identified 23 hematologic adverse events that were significantly over-reported compared to the general database, emphasizing the need for increased awareness and monitoring of these rare but potentially fatal toxicities in CAR T therapy patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. Song, Z., Tu, D., Tang, G., et al.[2023]

CAR T-cell therapy is a powerful immunotherapy that not only shows promise in treating various cancers but can also be adapted to target autoimmune diseases and infections like HIV.

The therapy utilizes engineered T cells that can recognize a wider range of targets compared to natural T cells, enhancing its potential effectiveness in diverse medical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of CAR-T cell technology in autoimmune diseases and human immunodeficiency virus infection treatment. Adabi, N., Pordel, S., Rezaee, MA., et al.[2023]

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Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]

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Associated Toxicities: Assessment and Management Related to CAR T-Cell Therapy. [2020]

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Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. [2023]

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High-Efficiency Generation of Antigen-Specific Primary Mouse Cytotoxic T Cells for Functional Testing in an Autoimmune Diabetes Model. [2020]