CAR T-cell Therapy for Blood Cancer
Palo Alto (17 mi)Overseen byJakub Svoboda, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Pennsylvania
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial aims to find the safest dose of specially modified immune cells for patients with certain types of cancers that have a specific marker. These cancers include Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Acute Lymphoblastic Leukemia. The modified cells are designed to seek out and destroy cancer cells with this marker.
Is the treatment huCART19-IL18 a promising treatment for blood cancer?Yes, huCART19-IL18 is a promising treatment for blood cancer because CAR T-cell therapies, like huCART19-IL18, have shown strong effectiveness in treating blood cancers, such as leukemia and lymphoma, by using modified immune cells to target and destroy cancer cells.24578
What safety data is available for CAR T-cell therapy for blood cancer?CAR T-cell therapy, including variants like huCART19-IL18, has shown effectiveness in treating blood cancers, but it is associated with significant safety concerns. Common adverse effects include cytokine release syndrome, neurologic toxicity, and on-target off-tumor toxicity. Strategies to mitigate these toxicities include suicide genes and synthetic Notch receptors. Clinical trials have reported severe neurologic toxicity in a small percentage of patients, and rare but fatal events like hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation. Post-approval studies have identified additional complications, such as cardiotoxicity and prolonged cytopenia. Management of these toxicities is crucial for patient safety.67101113
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you must stop taking your current medications. However, you cannot be on systemic steroids or immunosuppressant medications, and you must not have active GVHD requiring systemic therapy. It's best to discuss your specific medications with the trial team.
What data supports the idea that CAR T-cell Therapy for Blood Cancer (also known as: huCART19-IL18, huCART19-IL18) is an effective treatment?The available research shows that CAR T-cell therapy is effective for treating certain blood cancers, especially those that are difficult to treat with regular methods. For example, it has shown strong results in patients with B-cell acute lymphoblastic leukemia (B-ALL) and some success in chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL). This treatment works by using specially modified T-cells that target a specific protein called CD19 found on cancer cells. Compared to other treatments, CAR T-cell therapy has been particularly successful in cases where other treatments have failed, offering hope for patients with aggressive tumors.123912
Eligibility Criteria
Adults with CD19+ cancers like various leukemias and lymphomas, who have active disease despite previous treatments. They must be over 18, in fairly good health (ECOG 0 or 1), with decent organ function and no severe heart issues. Active infections or autoimmune diseases are deal-breakers, as is recent use of certain immune drugs.Inclusion Criteria
I cannot use or have not responded to standard CAR T cell therapy.
My condition worsened or didn't improve after a stem cell transplant.
I don't have active graft-versus-host disease and don't need immunosuppressants.
My chronic lymphocytic leukemia has recently relapsed.
My condition did not improve after initial treatment or I've had at least one treatment.
My CLL has transformed into a more aggressive form.
I don't have active graft-versus-host disease and don't need immunosuppressants.
I am fully active or can carry out light work.
My condition did not improve after 2 treatments and I can't have stem cell or CAR T cell therapy.
My condition worsened after 2 treatments, including a BTK inhibitor.
My condition worsened or didn't improve after a stem cell transplant.
I have minor or no breathing issues and my oxygen level is above 92% without assistance.
a. Your creatinine level is less than or equal to 1.6 mg/dl.
b. Your ALT/AST levels are less than or equal to 3 times the upper limit of normal range.
c. Your direct bilirubin level is less than or equal to 2.0 mg/dl, except if you have Gilbert's syndrome, where it can be up to 3.0 mg/dl.
d. You have good lung function with minimal difficulty breathing and pulse oxygen levels above 92% on room air.
e. Your left ventricle ejection fraction (LVEF) is at least 40%, confirmed by ECHO/MUGA.
My condition did not improve after two different treatments.
I have been diagnosed with a specific type of aggressive B-cell lymphoma.
My condition worsened or didn't improve after a stem cell transplant using my own cells.
My condition worsened or didn't improve after a stem cell transplant.
My cancer cells test positive for CD19.
My cancer is active, showing signs in blood, bone marrow, or measurable disease.
My condition relapsed after a stem cell transplant from a donor.
Exclusion Criteria
I am receiving treatment for ongoing GVHD.
I am on strong medication for an autoimmune disease, but I don't have MS.
I do not have active hepatitis B or C, or any uncontrolled infection.
I have severe heart problems that limit my daily activities.
I haven't taken immune checkpoint inhibitors in the last 4 months.
I have previously received huCART19 therapy.
I rely on steroids or immunosuppressant drugs.
Treatment Details
The trial is testing the safety of a new cell therapy called huCART19-IL18 for blood cancers that have a marker called CD19. The goal is to find the highest dose people can take without serious side effects.
17Treatment groups
Experimental Treatment
Group I: NHL Dose Level 5 (DL5)Experimental Treatment1 Intervention
3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group II: NHL Dose Level 4 (DL4)Experimental Treatment1 Intervention
7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group III: NHL Dose Level 3 (DL3)Experimental Treatment1 Intervention
3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group IV: NHL Dose Level 2 (DL2)Experimental Treatment1 Intervention
7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group V: NHL Dose Level 1b (DL1b)Experimental Treatment1 Intervention
3x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group VI: NHL Dose Level 1a (DL1a)Experimental Treatment1 Intervention
3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push
Group VII: NHL Dose Level -1 (DL-1)Experimental Treatment1 Intervention
7x10\^5 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 1a.
Group VIII: CLL Dose Level 5 (DL5)Experimental Treatment1 Intervention
3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group IX: CLL Dose Level 4 (DL4)Experimental Treatment1 Intervention
7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group X: CLL Dose Level 3 (DL3)Experimental Treatment1 Intervention
3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group XI: CLL Dose Level 2 (DL2)Experimental Treatment1 Intervention
7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group XII: CLL Dose Level 1b (DL1b)Experimental Treatment1 Intervention
3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 2.
Group XIII: ALL Dose Level 5 (DL5)Experimental Treatment1 Intervention
3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group XIV: ALL Dose Level 4 (DL4)Experimental Treatment1 Intervention
7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group XV: ALL Dose Level 3 (DL3)Experimental Treatment1 Intervention
3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group XVI: ALL Dose Level 2 (DL2)Experimental Treatment1 Intervention
7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
Group XVII: ALL Dose Level 1b (DL1b)Experimental Treatment1 Intervention
3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 2.
Find a clinic near you
Research locations nearbySelect from list below to view details:
University of PennsylvaniaPhiladelphia, PA
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Who is running the clinical trial?
University of PennsylvaniaLead Sponsor
References
Driving CAR-based T-cell therapy to success. [2021]T cells that have been genetically modified, activated, and propagated ex vivo can be infused to control tumor progression in patients who are refractory to conventional treatments. Early-phase clinical trials demonstrate that the tumor-associated antigen (TAA) CD19 can be therapeutically engaged through the enforced expression of a chimeric antigen receptor (CAR) on clinical-grade T cells. Advances in vector design, the architecture of the CAR molecule especially as associated with T-cell co-stimulatory pathways, and understanding of the tumor microenvironment, play significant roles in the successful treatment of medically fragile patients. However, some recipients of CAR(+) T cells demonstrate incomplete responses. Understanding the potential for treatment failure provides a pathway to improve the potency of adoptive transfer of CAR(+) T cells. High throughput single-cell analyses to understand the complexity of the inoculum coupled with animal models may provide insight into the therapeutic potential of genetically modified T cells. This review focuses on recent advances regarding the human application of CD19-specific CAR(+) T cells and explores how their success for hematologic cancers can provide a framework for investigational treatment of solid tumor malignancies.
Biology and clinical application of CAR T cells for B cell malignancies. [2023]Chimeric antigen receptor (CAR)-modified T cells have generated broad interest in oncology following a series of dramatic clinical successes in patients with chemorefractory B cell malignancies. CAR therapy now appears to be on the cusp of regulatory approval as a cell-based immunotherapy. We review here the T cell biology and cell engineering research that led to the development of second generation CARs, the selection of CD19 as a CAR target, and the preclinical studies in animal models that laid the foundation for clinical trials targeting CD19+ malignancies. We further summarize the status of CD19 CAR clinical therapy for non-Hodgkin lymphoma and B cell acute lymphoblastic leukemia, including their efficacy, toxicities (cytokine release syndrome, neurotoxicity and B cell aplasia) and current management in humans. We conclude with an overview of recent pre-clinical advances in CAR design that argues favorably for the advancement of CAR therapy to tackle other hematological malignancies as well as solid tumors.
Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. [2022]The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR)-modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (B-NHL). Early-phase clinical trials are currently assessing CAR T-cell safety and efficacy in additional malignancies. Here, we discuss clinical results from the largest series to date investigating CD19-targeted CAR T cells in B-ALL, CLL, and B-NHL, including discussion of differences in CAR T-cell design and production and treatment approach, as well as clinical efficacy, nature of severe cytokine release syndrome and neurologic toxicities, and CAR T-cell expansion and persistence. We additionally review the current and forthcoming use of CAR T cells in multiple myeloma and several solid tumors and highlight challenges and opportunities afforded by the current state of CAR T-cell therapies, including strategies to overcome inhibitory aspects of the tumor microenvironment and enhance antitumor efficacy.
Adoptive immunotherapy for hematological malignancies: Current status and new insights in chimeric antigen receptor T cells. [2018]Hematological malignancies frequently express cancer-associated antigens that are shared with normal cells. Such tumor cells elude the host immune system because several T cells targeted against self-antigens are removed during thymic development, and those that persist are eliminated by a regulatory population of T cells. Chimeric antigen receptor-modified T cells (CAR-Ts) have emerged as a novel modality for tumor immunotherapy due to their powerful efficacy against tumor cells. These cells are created by transducing genes-coding fusion proteins of tumor antigen-recognition single-chain Fv connected to the intracellular signaling domains of T cell receptors, and are classed as first-, second- and third-generation, differing on the intracellular signaling domain number of T cell receptors. CAR-T treatment has emerged as a promising approach for patients with hematological malignancies, and there are several works reporting clinical trials of the use of CAR-modified T-cells in acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, lymphoma, and in acute myeloid leukemia by targeting different antigens. This review reports the history of adoptive immunotherapy using CAR-Ts, the CAR-T manufacturing process, and T cell therapies in development for hematological malignancies.
Adoptive Immunotherapy for B-cell Malignancies Using CD19- Targeted Chimeric Antigen Receptor T-Cells: A Systematic Review of Efficacy and Safety. [2019]Adoptive infusion of chimeric antigen receptor transduced T- cells (CAR-T) is a powerful tool of immunotherapy for hematological malignancies, as evidenced by recently published and unpublished clinical results.
Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. [2020]Chimeric antigen receptor T (CAR-T) cell therapy is an emerging and effective cancer immunotherapy. Especially in hematological malignancies, CAR-T cells have achieved exciting results. Two Anti-CD19 CAR-T therapies have been approved for the treatment of CD19-positive leukemia or lymphoma. However, the application of CAR-T cells is obviously hampered by the adverse effects, such as cytokines release syndrome and on-target off-tumor toxicity. In some clinical trials, patients quitted the treatment of CAR-T cells due to life-threatening toxicity. Seeking to alleviate these toxicities or prevent the occurrence, researchers have developed a number of safety strategies of CAR-T cells, including suicide genes, synthetic Notch receptor, on-switch CAR, combinatorial target-antigen recognition, bispecific T cell engager and inhibitory CAR. This review summarized the preclinical studies and clinical trials of the safety strategies of CAR-T cells and their respective strengths and weaknesses.
Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. [2021]Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an effective treatment for B-cell lymphoma, but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-human clinical trial of T cells expressing the new anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of blood levels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphoma activity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR tested previously by our group, which contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells, whereas 50% of patients who received FMC63-28Z T cells experienced this degree of toxicity (P = 0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63-28Z. Lower levels of cytokines were detected in blood from patients who received Hu19-CD828Z T cells than in blood from those who received FMC63-28Z T cells, which could explain the lower level of neurologic toxicity associated with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.
Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study. [2022]Anti-CD19 chimeric antigen receptor (CAR) T cell (CART19) therapy holds great promise in the treatment of hematological malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CART19 therapy.
Overcoming key challenges in cancer immunotherapy with engineered T cells. [2021]A number of clinical trials are currently testing chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells for the treatment of haematologic malignancies and selected solid tumours, and CD19-CAR-T cells have produced impressive clinical responses in B-cell malignancies. Here, we summarize the current state of the field, highlighting the key aspects required for the optimal application of CAR and TCR-engineered T cells for cancer immunotherapy.
Complications after CD19+ CAR T-Cell Therapy. [2020]Clinical trials demonstrated that CD19+ chimeric antigen receptor (CAR) T-cells can be highly effective against a number of malignancies. However, the complete risk profile of CAR T-cells could not be defined in the initial trials. Currently, there is emerging evidence derived from post approval studies in CD19+ CAR T-cells demonstrating both short-term and medium-term effects, which were unknown at the time of regulatory approval. Here, we review the incidence and the current management of CD19+ CAR T-cell complications. We highlight frequently occurring events, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cardiotoxicity, pulmonary toxicity, metabolic complications, secondary macrophage-activation syndrome, and prolonged cytopenia. Furthermore, we present evidence supporting the hypothesis that CAR T-cell-mediated toxicities can involve any other organ system and we discuss the potential risk of long-term complications. Finally, we discuss recent pre-clinical and clinical data shedding new light on the pathophysiology of CAR T-cell-related complications.
Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. [2023]Hematotoxicity is the most common long-term adverse event (AE) after chimeric antigen receptor T-cell (CAR T) therapy. However, patients who receive CAR T therapy in pivotal clinical trials are subjected to restrictive selection criteria, and this means that rare but fatal toxicities are underestimated. Here, we systematically analyzed CAR T-associated hematologic AE using the US Food and Drug Administration Adverse Event Reporting System (FAERS) between January 2017 and December 2021. Disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC); the lower limit of the ROR and IC 95% confidence interval (CI) (ROR025 and IC025) exceeding one and zero was considered significant, respectively. Among the 105,087,611 reports in FAERS, 5,112 CAR T-related hematotoxicity reports were identified. We found 23 significant over-reporting hematologic AE (ROR025 >1) compared to the full database, of which hemophagocytic lymphohistiocytosis (HLH; n=136 [2.7%], ROR025 = 21.06), coagulopathy (n=128 [2.5%], ROR025 = 10.43), bone marrow failure (n=112 [2.2%], ROR025 = 4.88), disseminated intravascular coagulation (DIC; n=99 [1.9%], ROR025 = 9.64), and B-cell aplasia (n=98 [1.9%], ROR025 = 118.16, all IC025 > 0) were highly under-reported AE in clinical trials. Importantly, HLH and DIC led to mortality rates of 69.9% and 59.6%, respectively. Lastly, hematotoxicity-related mortality was 41.43%, and 22 death-related hematologic AE were identified using LASSO regression analysis. These findings could help clinicians in the early detection of those rarely reported but lethal hematologic AE, thus reducing the risk of severe toxicities for CAR T recipients.
Recent Prospective in CAR T-Based Therapy for Solid and Hematological Malignancies. [2023]Given that CAR-T cell therapy is effective in CD19-positive blood malignancies, it offers great hope for a variety of aggressive tumors that have thus far shown very little response to available therapies [...].
Management and Prevention of Cellular-Therapy-Related Toxicity: Early and Late Complications. [2023]Chimeric Antigen Receptor T (CAR-T) cell therapy has dramatically changed prognosis and treatment of relapsed and refractory hematologic malignancies. Currently the 6 FDA approved products target various surface antigens. While CAR-T therapy achieves good response, life-threatening toxicities have been reported. Mechanistically, can be divided into two categories: (1) toxicities related to T-cell activation and release of high levels of cytokines: or (2) toxicities resulting from interaction between CAR and CAR targeted antigen expressed on non-malignant cells (i.e., on-target, off-tumor effects). Variations in conditioning therapies, co-stimulatory domains, CAR T-cell dose and anti-cytokine administration, pose a challenge in distinguishing cytokine mediated related toxicities from on-target, off-tumor toxicities. Timing, frequency, severity, as well as optimal management of CAR T-cell-related toxicities vary significantly between products and are likely to change as newer therapies become available. Currently the FDA approved CARs are targeted towards the B-cell malignancies however the future holds promise of expanding the target to solid tumor malignancies. Further highlighting the importance of early recognition and intervention for early and late onset CAR-T related toxicity. This contemporary review aims to describe presentation, grading and management of commonly encountered toxicities, short- and long-term complications, discuss preventive strategies and resource utilization.