MUC1-Activated T Cells for Ovarian Cancer

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must not be taking: Steroids, Antiretrovirals, Investigational agents, others

Disqualifiers: CNS metastases, Plasma cell leukemia, others

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

Compensation: Varies

Number of Visits: 31

Duration: 4 weeks

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, best dose of MUC1-activated T cells in treating patients with ovarian cancer that has come back after a period of improvement (relapsed) or that remains despite treatment (resistant). T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this study will come from the patient and are made in a laboratory to recognize MUC1, a protein on the surface of tumor cells that plays a key role in tumor cell growth. These MUC1-activated T cells may help the body's immune system identify and kill MUC1 expressing ovarian tumor cells.

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

The trial does not specify if you need to stop taking your current medications. However, if you are on certain treatments like high-dose steroids or other investigational agents, you may not be eligible to participate.

What data supports the effectiveness of the treatment Autologous MUC1-activated T-cells for ovarian cancer?

Research shows that using MUC1-activated T-cells in ovarian cancer patients can lead to increased survival and reduced tumor markers. Some patients experienced prolonged survival, and the treatment was associated with enhanced immune responses, suggesting it may help the body fight the cancer more effectively. ^{1 2 3 4 5}

Is MUC1-activated T cell therapy safe for humans?

Research indicates that long-term administration of activated autologous lymphocytes, including MUC1-activated T cells, does not induce autoimmune diseases in cancer patients. Mild transient fever was noted as a possible side effect, but no other adverse reactions were reported. ^{4 6 7 8 9}

What makes the MUC1-activated T cells treatment unique for ovarian cancer?

The MUC1-activated T cells treatment is unique because it uses the patient's own immune cells, specifically targeting the MUC1 protein that is overexpressed in ovarian cancer cells, to enhance the body's immune response against the cancer. This personalized approach aims to improve survival by modulating immune responses and reducing tumor markers, which is different from standard chemotherapy or radiation treatments. ^{1 4 5 10 11}

Research Team

Brenda J Ernst, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for patients with ovarian cancer that has returned or resisted treatment. Participants must have a specific protein, MUC1, on their tumor cells. They will undergo various imaging tests and procedures like leukapheresis to prepare T-cells.

Inclusion Criteria

Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria on study entry

Provide written informed consent

Willingness to provide mandatory blood specimens and biopsy tissue for correlative research

Exclusion Criteria

Patients receiving any other investigational agent which could be considered a treatment for the neoplasm

I have been diagnosed with another cancer within the last 4 years.

I have untreated or ongoing brain metastases.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Leukapheresis and Lymphodepletion

Patients undergo leukapheresis and receive cyclophosphamide or bendamustine for lymphodepletion

1 week

Multiple visits (in-person)

Treatment

Patients receive MUC1-activated T cells intravenously and undergo various imaging and blood sample collections

4 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Visits at 30 and 60 days from day 28, then every 3 months

Treatment Details

Interventions

• Autologous MUC1-activated T-cells

Trial Overview The trial is testing the safety and optimal dosage of lab-made MUC1-activated T cells in treating relapsed/resistant ovarian cancer. These are patient's own immune cells modified to target and kill cancer cells expressing the MUC1 protein.

Participant Groups

Group I: Treatment (MUC1-activated T cells, lymphodepletion) Experimental Treatment 10 Interventions

Patients undergo leukapheresis over 4 hours within 14 days after registration. Patients receive cyclophosphamide IV over 60 minutes on days -5 to -3 or bendamustine IV over 10 minutes on days -5 and -4 or -4 and -3. Patients receive MUC1-activated T cells IV over 10-60 minutes on day 0 or days 0 and 21. Patients also undergo ECHO or MUGA during screening, and blood sample collection throughout the trial. In addition, patients may undergo CT, MRI, or PET/CT as clinically indicated throughout the trial. Patients may also undergo collection of ascites on study and during follow up.

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

In a new tumor model for ovarian cancer using MUC1-expressing cells, anti-PD-L1 antibody treatment significantly increased T cell infiltration and improved survival rates in mice, indicating its potential efficacy in advanced ovarian cancer.

The study found that earlier treatment and more frequent doses of anti-PD-L1 were necessary to enhance T cell responses and prolong survival, suggesting that timing and dosage are critical factors for optimizing immune checkpoint blockade therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model. Mony, JT., Zhang, L., Ma, T., et al.[2018]

In a phase I/II study involving patients with recurrent ovarian cancer, adoptive T cell therapy using IL-10- and IFN-γ-producing CD4 effector cells showed promising results, with some patients experiencing prolonged survival and one remaining disease-free after treatment.

The study found that the effectiveness of the therapy was linked to specific ratios of TReg cell subpopulations rather than their overall numbers, suggesting that the balance of these immune cells plays a crucial role in enhancing long-term tumor immunity and T cell memory.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy with IL-10- and IFN-γ-producing CD4 effector cells modulate "Natural" and "Inducible" CD4 TReg cell subpopulation levels: observations in four cases of patients with ovarian cancer. Dobrzanski, MJ., Rewers-Felkins, KA., Samad, KA., et al.[2021]

Adoptive cell therapy using human interleukin 2-activated large granular lymphocytes and T-cells significantly extended the survival of nude mice with ovarian cancer, with mean survival times increasing from 30 to 60 days.

Monocytes, even when activated with gamma-interferon, did not improve survival, suggesting that not all immune cell types are equally effective in this therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive cellular immunotherapy of human ovarian carcinoma xenografts in nude mice. Ortaldo, JR., Porter, HR., Miller, P., et al.[2003]

Adoptive T cell immunotherapy using autologous MUC1 peptide-stimulated CD4(+) effector cells in ovarian cancer patients showed promising results, with some patients experiencing diminished tumor markers and enhanced survival rates after three treatment cycles.

Long-term survivors exhibited increased levels of specific T cell populations that correlated with better outcomes, suggesting that the balance of regulatory T cells may play a crucial role in sustaining tumor immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous MUC1-specific Th1 effector cell immunotherapy induces differential levels of systemic TReg cell subpopulations that result in increased ovarian cancer patient survival. Dobrzanski, MJ., Rewers-Felkins, KA., Quinlin, IS., et al.[2021]

A new preclinical mouse model for MUC1-positive ovarian tumors was developed, which closely mimics human ovarian cancer, showing increased metastasis and immune suppression, making it a valuable tool for testing therapies.

Vaccination with dendritic cells loaded with a MUC1 peptide effectively activates the immune response and prolongs survival in these mice, highlighting MUC1 as a promising target for immune-based treatments in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunobiology of human mucin 1 in a preclinical ovarian tumor model. Budiu, RA., Elishaev, E., Brozick, J., et al.[2021]

In a study involving six multiple myeloma patients, cytotoxic T lymphocyte (CTL) lines were successfully induced from two patients, demonstrating the potential to target MUC1, a tumor-associated antigen, in myeloma and breast carcinoma cells.

The CTL lines showed effective cytotoxicity against MUC1+ cancer cells, and their activity was specifically inhibited by antibodies targeting MUC1, indicating that these CTLs can recognize and attack cancer cells expressing this antigen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic T lymphocytes derived from bone marrow mononuclear cells of multiple myeloma patients recognize an underglycosylated form of MUC1 mucin. Noto, H., Takahashi, T., Makiguchi, Y., et al.[2019]

In a study involving 22 patients with advanced cancers, treatment with activated autologous lymphocytes showed no evidence of inducing autoimmune disease, as most patients maintained normal levels of autoimmune markers throughout the treatment.

While mild transient fever was noted as an adverse event, no significant autoimmune symptoms were observed, suggesting that this therapy is relatively safe in terms of autoimmune side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term intravenous administration of activated autologous lymphocytes for cancer patients does not induce antinuclear antibody and rheumatoid factor. Yamaguchi, T., Bamba, K., Kitayama, A., et al.[2017]

Immunization of MUC1.Tg mice with human MUC1 antigen led to the production of anti-MUC1 antibodies but did not trigger a cytotoxic T cell response, indicating a potential limitation in the immune response against MUC1-associated tumors.

The study found that immunization resulted in decreased levels of CD8+ T cells and down-regulation of T cell receptors, suggesting that tolerance to the MUC1 antigen may involve T cell suppression in these mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell suppression as a mechanism for tolerance to MUC1 antigen in MUC1 transgenic mice. Chen, D., Koido, S., Li, Y., et al.[2019]

MUC1 glycoprotein is frequently overexpressed in various cancers, making it a promising target for antitumor immunotherapy, with T-cell responses observed in both HLA-restricted and unrestricted manners.

Encouraging results from phase II/III clinical trials of MUC1-based vaccines indicate their potential effectiveness in inducing specific cytotoxic T cell responses against tumors, although some animal studies suggest the need to monitor for tolerogenic responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MUC1-specific cytotoxic T lymphocytes in cancer therapy: induction and challenge. Roulois, D., Grégoire, M., Fonteneau, JF.[2021]

MUC1 is overexpressed in more than 90% of advanced epithelial ovarian cancers (EOCs) and their metastatic lesions, while it is rarely found in normal ovarian tissues, indicating its potential as a tumor marker.

The high levels of MUC1 expression are significantly associated with worse progression parameters of EOC, such as tumor stage and presence of ascites, suggesting that targeting MUC1 could be a promising strategy for treating recurrent metastatic EOC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of MUC1 in primary and metastatic human epithelial ovarian cancer and its therapeutic significance. Wang, L., Ma, J., Liu, F., et al.[2022]

A specific population of tissue-resident memory T cells (TIM-3/CXCL13-positive) was identified in epithelial ovarian cancer (EOC), which is associated with improved survival in patients, based on analysis of around 175 patients with high-grade serous EOC.

The study suggests that combining TIM-3 and PD-1 blockade therapies could enhance anti-cancer immunity in EOC, particularly since CXCL13-positive CD8 T cells are linked to better responses to existing immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival. Vlaming, M., Bilemjian, V., Freile, JÁ., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Immunotherapy with IL-10- and IFN-γ-producing CD4 effector cells modulate "Natural" and "Inducible" CD4 TReg cell subpopulation levels: observations in four cases of patients with ovarian cancer. [2021]

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

Adoptive cellular immunotherapy of human ovarian carcinoma xenografts in nude mice. [2003]

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

Autologous MUC1-specific Th1 effector cell immunotherapy induces differential levels of systemic TReg cell subpopulations that result in increased ovarian cancer patient survival. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Immunobiology of human mucin 1 in a preclinical ovarian tumor model. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Cytotoxic T lymphocytes derived from bone marrow mononuclear cells of multiple myeloma patients recognize an underglycosylated form of MUC1 mucin. [2019]

7. Greece pubmed.ncbi.nlm.nih.gov

Long-term intravenous administration of activated autologous lymphocytes for cancer patients does not induce antinuclear antibody and rheumatoid factor. [2017]

8. Netherlands pubmed.ncbi.nlm.nih.gov

T cell suppression as a mechanism for tolerance to MUC1 antigen in MUC1 transgenic mice. [2019]

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

MUC1-specific cytotoxic T lymphocytes in cancer therapy: induction and challenge. [2021]

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

Expression of MUC1 in primary and metastatic human epithelial ovarian cancer and its therapeutic significance. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Tumor infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival. [2022]