CAR T Cell Immunotherapy for Pancreatic Cancer

Overseen By Mark O'Hara, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Active cancer, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day per infusion, with additional infusions possible between 21-42 days apart

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called huCART-meso cells, a type of CAR T cell immunotherapy, to determine its safety and practicality for individuals with pancreatic cancer that cannot be removed or has metastasized. The trial explores different administration methods, including delivery through the bloodstream or directly to the liver, to identify the most effective approach. Participants must have a confirmed diagnosis of pancreatic adenocarcinoma that is inoperable or has spread and must have previously tried at least one standard treatment without success. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy or systemic steroids, you may need to stop them at least 4 weeks before joining the trial.

Is there any evidence suggesting that huCART-meso cells are likely to be safe for humans?

Research has shown that huCART-meso cells, a type of CAR T cell therapy, have been safe in earlier studies involving patients with advanced pancreatic cancer. Most participants tolerated the treatment well. However, some experienced serious lung problems when receiving higher doses through an IV. This indicates that while the treatment is generally safe, risks exist, particularly with higher doses. Considering these potential risks and benefits is important when deciding to join a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about huCART-meso cell therapy because it represents a novel approach to treating pancreatic cancer. Unlike traditional treatments like chemotherapy and radiation, which target cancer cells broadly, huCART-meso cells are a form of CAR T cell therapy that specifically targets mesothelin, a protein often overexpressed in pancreatic cancer cells. This precision targeting could lead to more effective cancer cell destruction while minimizing damage to healthy cells. Additionally, the various delivery methods, including intravenous, intrahepatic, and intraperitoneal infusions, offer flexibility in treatment administration, potentially enhancing effectiveness and patient outcomes.

What evidence suggests that huCART-meso cells could be an effective treatment for pancreatic cancer?

This trial will evaluate the safety and effectiveness of huCART-meso cells for pancreatic cancer. Studies have shown that huCART-meso cells are safe for patients. However, research indicates that while these cells can grow in the body, they have not been very effective in fighting cancer. In earlier studies, patients with pancreatic cancer did not experience significant improvements from this treatment. Scientists continue to investigate why these cells aren't working as well as expected. So far, the treatment has not been proven effective for pancreatic cancer. Participants in this trial will receive huCART-meso cells through various methods, including intravenous, intrahepatic, and intraperitoneal infusions, to explore potential improvements in outcomes. ^{1 3 4 6 7}

Who Is on the Research Team?

Mark O'Hara, MD

Principal Investigator

Assistant Professor of Medicine, Penn Medicine

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced pancreatic cancer that can't be surgically removed or has spread, and who have already tried at least one chemotherapy. They must have a certain level of health and organ function, not have other active cancers or infections like HIV or hepatitis, no recent immunosuppressants use, and agree to birth control methods.

Inclusion Criteria

Subjects of reproductive potential must agree to use acceptable birth control methods

My advanced disease has not worsened on first-line chemotherapy.

Measurable disease as defined by RECIST 1.1 criteria for Cohorts 1-3 and -1

Exclusion Criteria

History of allergy or hypersensitivity to study product excipients

Pregnant or breastfeeding women

I need extra oxygen to help me breathe.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of lentiviral transduced huCART-meso cells via different delivery methods depending on cohort assignment

1 day per infusion, with additional infusions possible between 21-42 days apart

Multiple visits for infusions and assessments

Safety Monitoring

Participants are monitored for dose-limiting toxicities (DLTs) and adverse events

21 days post-infusion for initial safety follow-up

Regular visits for safety assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• huCART-meso cells

Trial Overview The study tests the safety of huCART-meso cells delivered either through the veins or directly into the tumor in patients with pancreatic cancer. It's an early-phase trial (Phase I) focusing on whether this method is safe and doable.

How Is the Trial Designed?

Group I: Cohort 4 - huCART meso cells via intrahepatic infusion (hepatic arterial infusion) Experimental Treatment 1 Intervention

Subjects will receive a single dose of of 1-3x10\^7 cells/m\^2 lentiviral transduced huCART-meso cells on day 0 following a minimum 1 week washout from standard care chemotherapy. This initial intrahepatic infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous (IV) administration at the same dose level, given between 21-42 days apart.

Group II: Cohort 3 - huCART meso cells via intrahepatic infusion (hepatic arterial infusion) Experimental Treatment 1 Intervention

Permanently closed

Group III: Cohort 2 - huCART meso cells via intraperitoneal infusion (IP) Experimental Treatment 1 Intervention

Permanently closed

Group IV: Cohort 1: huCART-meso cells via intravenous infusion (IV). Experimental Treatment 1 Intervention

Subjects will receive a single dose of 1-3x10\^7/m\^2 lentiviral transduced huCART-meso cells on day 0 via intravenous infusion.

Group V: Cohort -1: low dose huCART-meso cells via intravenous infusion Experimental Treatment 1 Intervention

In the event that 2 DLTs occur among subjects enrolled in Cohort 1, then enrollment in Cohort 1 will be stopped and the dose will be de-escalated by 10-fold to 1-3x10\^6 cells/m\^2. Subjects will receive a single dose of 1-3x10\^6 cells/m\^2 lentiviral transduced huCART-meso cells on day 0.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

Adoptive cell therapy using CAR-engineered T cells shows promise as a safe treatment option for patients with pancreatic ductal adenocarcinoma, indicating it may help restore effective immune surveillance against tumors.

Early results suggest that CAR T cells not only have the ability to attack tumors directly but also stimulate the body's own immune system to fight cancer, enhancing overall anti-tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered chimeric antigen receptor-expressing T cells for the treatment of pancreatic ductal adenocarcinoma. Beatty, GL.[2023]

The pilot study involving 3 patients with chemotherapy-refractory pancreatic ductal adenocarcinoma (PDAC) demonstrated that administering CAR-modified T cells targeting mesothelin and CD19 was safe and well tolerated, with no dose-limiting toxicities observed.

While the treatment successfully depleted B cells in all subjects and maintained this depletion for at least 28 days, it did not enhance the persistence of the mesothelin-targeted CAR T cells, indicating that further optimization may be needed for improved efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic Pancreatic Cancer. Ko, AH., Jordan, AC., Tooker, E., et al.[2023]

Meso-CART cells, engineered T cells targeting mesothelin, showed promising anti-tumor effects against pancreatic cancer, particularly in eliminating lung metastases in mice, indicating potential for treating advanced stages of the disease.

This study is the first to demonstrate that meso-CART cells can effectively target and reduce distant metastases, suggesting they could be a viable immunotherapy option for patients with mesothelin-positive pancreatic tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered T lymphocytes eliminate lung metastases in models of pancreatic cancer. Sun, Q., Zhou, S., Zhao, J., et al.[2019]

Pancreatic cancer is projected to become the second leading cause of cancer-related deaths in the U.S. by 2030, highlighting the urgent need for new treatment options, as current immunotherapies have shown limited effectiveness.

Chimeric antigen receptor (CAR) T cell therapy is emerging as a promising treatment for pancreatic cancer, utilizing genetically engineered T cells to target specific cancer-associated antigens, with ongoing preclinical and early clinical trials exploring its efficacy and potential combinations with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Potential of CAR T Cell Therapy in Pancreatic Cancer. Akce, M., Zaidi, MY., Waller, EK., et al.[2022]

A phase I trial of a multiantigen-specific T-cell therapy using patients' own nonengineered T cells showed safety and potential effectiveness in treating advanced pancreatic cancer.

Patients receiving this therapy, alongside chemotherapy, exhibited responses, suggesting that this approach could enhance treatment outcomes for those with advanced disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy Shows Promise in Pancreatic Cancer. [2020]

In a phase I study involving 6 patients with chemotherapy-refractory metastatic pancreatic ductal adenocarcinoma (PDAC), engineered T cells expressing a CAR targeting mesothelin were administered safely, with no severe side effects like cytokine release syndrome or neurologic symptoms.

While the treatment showed some promise, with disease stabilization in 2 patients and a significant reduction in tumor activity in one, it also highlighted the inherent resistance of PDAC to T-cell-mediated immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. Beatty, GL., O'Hara, MH., Lacey, SF., et al.[2022]

The engineered mesothelin-targeting chimeric antigen receptor T cells (mesoCAR T) showed strong effectiveness in killing pancreatic cancer cells with high mesothelin expression in laboratory tests, indicating a targeted approach to treatment.

In a mouse model, mesoCAR T cells significantly reduced tumor growth and demonstrated a favorable safety profile, with minimal damage to major organs, suggesting potential for clinical use in treating pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered CAR T cells targeting mesothelin by piggyBac transposon system for the treatment of pancreatic cancer. He, J., Zhang, Z., Lv, S., et al.[2021]

Blocking Interleukin-10 in the tumor microenvironment significantly enhances the effectiveness of mesothelin-chimeric antigen receptor T cell therapy, as it restores the secretion of key cytokines like interferon γ and granzyme B that are essential for killing cancer cells.

In experiments, T cells exposed to pancreatic cancer cell-conditioned medium showed reduced cytotoxicity, but this effect was notably reversed when Interleukin-10 was depleted, suggesting a promising strategy to improve immunotherapy outcomes in pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of Interleukin-10 in the tumor microenvironment can restore mesothelin chimeric antigen receptor T cell activity in pancreatic cancer in vitro. Batchu, RB., Gruzdyn, OV., Mahmud, EM., et al.[2021]

The study developed dual-receptor CAR-modified T cells (dCAR-T) that effectively target pancreatic cancer cells expressing both carcino-embryonic antigen (CEA) and mesothelin (MSLN), demonstrating high anti-tumor activity in vitro and in vivo.

dCAR-T cells showed significant cytotoxicity against tumor cells with both antigens while sparing those with only one, reducing the risk of 'on-target, off-tumor' toxicity and allowing for more precise CAR-T cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombination of a dual-CAR-modified T lymphocyte to accurately eliminate pancreatic malignancy. Zhang, E., Yang, P., Gu, J., et al.[2021]

Engineered T cells targeting mesothelin, a protein overproduced by pancreatic tumors, effectively infiltrated and destroyed cancer cells in mice.

The treatment significantly improved survival times in the mice, nearly doubling their lifespan, indicating a promising approach for pancreatic cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T Cells Target Pancreatic Tumors. Leslie, M.[2021]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S266637912500374X

Clinical and molecular dissection of CAR T cell resistance ... Here, we report the clinical results of a phase 1 study of huCART-meso cells in patients with metastatic PDAC. To better understand responses, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03323944

CAR T Cell Immunotherapy for Pancreatic Cancer This is a Phase I study evaluating the safety and feasibility of lentiviral transduced huCART-meso cells in up to 4 cohorts.

3. jitc.bmj.com jitc.bmj.com/content/11/Suppl_1/A760

671 Phase 1 trial of human chimeric antigen receptor ... Here we report interim results for three patients with epithelial ovarian- and pancreatic cancer treated with an intravenous infusion of VCN-01, ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6838875/

Phase I Study of Lentiviral-Transduced Chimeric Antigen ... CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti- ...

5. acir.org acir.org/weekly-digests/2025/august/overcoming-dysfunctional-car-t-in-pancreatic-cancer

Overcoming dysfunctional CAR-T in pancreatic cancer Together, this study showed that while treatment with huCART-meso in patients with advanced PDAC was safe, it was not effective. Some reasons ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12490220/

Clinical and molecular dissection of CAR T cell resistance in ... Aznar and Good et al. report a phase 1 trial of anti-mesothelin CAR T cells in pancreatic cancer, demonstrating safety but limited efficacy.

7. sciencedirect.com sciencedirect.com/science/article/pii/S1525001623003167

Two cases of severe pulmonary toxicity from highly active ... We observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1–3 × 10 8 T cells per m 2 ).