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

18 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment huCART-meso cells for pancreatic cancer?

Research shows that huCART-meso cells, which are engineered to target a protein called mesothelin found in pancreatic tumors, have been effective in animal studies by entering tumors and destroying cancer cells, nearly doubling survival times. In a small human trial, this treatment stabilized the disease in some patients and significantly reduced tumor activity in one patient, suggesting potential antitumor effects. ^{1 2 3 4 5}

Is CAR T cell immunotherapy safe for humans?

Research shows that CAR T cell therapy targeting mesothelin in pancreatic cancer patients is generally safe, with no severe side effects like cytokine release syndrome (a severe immune reaction) or neurological symptoms reported. In studies, the treatment was well tolerated, and no dose-limiting toxicities (serious side effects that prevent increasing the dose) were observed. ^{1 4 5 6 7}

How is the CAR T Cell Immunotherapy for Pancreatic Cancer treatment different from other treatments?

This treatment is unique because it uses genetically engineered T cells, called CAR T cells, to specifically target and attack cancer cells that express a protein called mesothelin, which is often found in pancreatic cancer. Unlike traditional treatments, this approach aims to harness the body's immune system to fight the cancer, offering a novel option for a condition with limited effective treatments. ^{1 4 8 9 10}

What is the purpose of this trial?

Phase I study to establish the safety and feasibility of both intravenous administration and local delivery of lentiviral transduced huCART-meso cells in patients with histologically confirmed unresectable or metastatic pancreatic adenocarcinoma

Research Team

Mark O'Hara, MD

Principal Investigator

Assistant Professor of Medicine, Penn Medicine

Eligibility Criteria

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

I have tried at least one standard chemotherapy for my advanced disease.

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

Exclusion Criteria

I need extra oxygen to help me breathe.

I have had treatment with gene-modified cells before.

History of allergy or hypersensitivity to study product excipients

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Engineered T lymphocytes eliminate lung metastases in models of pancreatic cancer. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

T Cells Target Pancreatic Tumors. [2021]

3. United States 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. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic Pancreatic Cancer. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Engineered CAR T cells targeting mesothelin by piggyBac transposon system for the treatment of pancreatic cancer. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Recombination of a dual-CAR-modified T lymphocyte to accurately eliminate pancreatic malignancy. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

The Potential of CAR T Cell Therapy in Pancreatic Cancer. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

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

10. United States pubmed.ncbi.nlm.nih.gov

Immunotherapy Shows Promise in Pancreatic Cancer. [2020]