MUC1-Activated T Cells for Ovarian Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Female
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Mayo Clinic
Must not be taking: Steroids, Antiretrovirals, Investigational agents, others
Disqualifiers: CNS metastases, Plasma cell leukemia, others
No Placebo Group
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.
12345Is 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.
46789What 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.
1451011Eligibility 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
+20 more
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.
+11 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (MUC1-activated T cells, lymphodepletion)Experimental Treatment10 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo Clinic in ArizonaScottsdale, AZ
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Who Is Running the Clinical Trial?
Mayo ClinicLead Sponsor
References
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]Monoclonal antibodies that block inhibitory immune checkpoint molecules and enhance anti-tumor responses show clinical promise in advanced solid tumors. Most of the preliminary evidence on therapeutic efficacy of immune checkpoint blockers comes from studies in melanoma, lung and renal cancer. To test the in vivo potential of programmed death-ligand 1 (PD-L1) blockade in ovarian cancer, we recently generated a new transplantable tumor model using human mucin 1 (MUC1)-expressing 2F8 cells. The MUC1 transgenic (MUC1.Tg) mice develop large number of intraperitoneal (IP) tumors following IP injection of 8 × 10(5) syngeneic 2F8 cells. The tumors are aggressive and display little T cell infiltration. Anti-PD-L1 antibody was administered IP every 2 weeks (200 μg/dose) for a total of three doses. Treatment was started 21 days post-tumor challenge, a time point which corresponds to late tumor stage. The anti-PD-L1 treatment led to substantial T cell infiltration within the tumor and significantly increased survival (p = 0.001) compared to isotype control-treated mice. When the same therapy was administered to wild-type mice challenged with 2F8 tumors, no survival benefit was observed, despite the presence of high titer anti-MUC1 antibodies. However, earlier treatment (day 11) and higher frequency of IP injections restored the T cell responses and led to prolonged survival. Splenocyte profiling via Nanostring using probes for 511 immune genes revealed a treatment-induced immune gene signature consistent with increased T cell-mediated immunity. These findings strongly support further preclinical and clinical strategies exploring PD-L1 blockade in ovarian cancer.
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]Adoptive T cell therapy for cancer patients optimally requires participation of CD4 T cells. In this phase I/II study, we assessed the therapeutic effects of adoptively transferred IL-10- and IFN-γ-producing CD4 effector cells in patients with recurrent ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4 effector cell generation, we show that three monthly treatment cycles of autologous T cell restimulation and local intraperitoneal re-infusion-modulated T cell-mediated immune responses that were associated with enhanced patient survival. One patient remains disease-free, another patient experienced prolonged survival for nearly 16 months with recurrent disease, and two patients expired within 3-5 months following final infusion. Prolonged survivors showed elevated levels of systemic CD3(+)CD4(+)CD25(+) and CD3(+)CD4(+)CD25(-) T cells when compared to that of pre-treatment levels and similarly treated short-term survivors. Such cell populations among these patients contained variable levels of "Inducible" Tr1 (CD4(+)CD25(-)FoxP3(-)IL-10(+)) and "Natural" (CD4(+)CD25(+)CD45RO(+)FoxP3(+)) TReg cell numbers and ratios that were associated with prolonged and/or disease-free survival. Moreover, peptide-restimulated T cells from these patients showed an elevation in both IFN-γ production, memory cell phenotype, and select TNF family ligands associated with enhanced T cell survival and apoptosis-inducing activities. This suggests that intraperitoneally administered Th1-like cells, producing elevated levels of IL-10, may require and/or induce differential levels of distinct systemic TReg subpopulations that influence, in part, long-term tumor immunity and enhanced memory/effector CD4-mediated therapeutic potentials. Furthermore, treatment efficacy and enhanced memory cell phenotype did not appear to be dependent on TReg cell numbers but upon ratios of "Inducible" and "Natural" TReg subpopulations.
Adoptive cellular immunotherapy of human ovarian carcinoma xenografts in nude mice. [2003]Adoptive cell therapy with various purified populations of human lymphoid and monocytoid effector cells which have been in vitro activated with recombinant interleukin 2 and gamma-interferon was performed in an in vivo nude mouse model of human ovarian cancer. Administration i.p. of human interleukin 2-activated populations of large granular lymphocytes resulted in a significant extension of mean survival time (30 to 60 days) in this ovarian carcinoma model. In addition, T-cells activated with interleukin 2, in a similar fashion to large granular lymphocytes, also significantly prolonged survival of animals with ovarian carcinoma. In contrast, monocytes, with or without gamma-interferon activation, did not improve survival of tumor-bearing mice. In vitro results using direct isotopic release assays to measure efficacy of effectors against the ovarian cancer cells before and after activation, especially the activated natural killer cells, paralleled the effects on survival in the nude mouse model. However, the results with T-cells were somewhat inconsistent in vitro regarding their in vivo efficacy. We assume this is due to a delayed generation of activated killing in T-cells that is generated in vivo. These experimental results in this model system of human ovarian cancer indicate that transfer of autologous activated cells may have a role in the treatment of ovarian cancer patients.
Autologous MUC1-specific Th1 effector cell immunotherapy induces differential levels of systemic TReg cell subpopulations that result in increased ovarian cancer patient survival. [2021]Adoptive T cell immunotherapy using autologous lymphocytes is a viable treatment for patients with cancer and requires participation of Ag-specific CD4 and CD8 T cells. Here, we assessed the immunotherapeutic effects of autologous MUC1 peptide-stimulated CD4(+) effector cells following adoptive transfer in patients with ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4(+)/Th1 effector cell generation, we show that three monthly treatment cycles of peripheral blood T cell restimulation and intraperitoneal re-infusion selectively modulated endogenous T cell-mediated immune responses that correlated with diminished serum CA125 tumor marker levels and enhanced patient survival. One patient remains disease-free, another patient survived long-term for nearly 16 months with recurrent disease and two patients expired within 3-5 months following final infusion. Although PBL from all patients showed elevated MUC1 cytolytic activity following therapy, such responses did not correlate with therapeutic efficacy. Long-term survivors showed elevated levels of systemic memory (CD45RO) and naïve (CD45RA) CD3/CD4/CD25(+) T cells when compared to that of pre-treatment levels and similarly treated short-term survivors. Such cells co-expressed different levels of Foxp3 and CTLA-4 that resulted in progressively lower systemic Foxp3/CTLA-4 memory T cell ratios that further correlated with disease-free survival. Lastly, these patients showed elevated levels of MUC1-specific T cells expressing the CCR5 and CCR1 chemokine receptors and the chemokine CCL4 associated with Th1 cell differentiation/memory. We suggest that effective immunotherapy with autologous MUC1-stimulated CD4(+) effector cells induces differential levels of systemic "Ag-experienced" and "Ag-inexperienced" CD4/CD25(+) TReg cell subpopulations that influence long-term tumor immunity in ovarian cancer patients.
Immunobiology of human mucin 1 in a preclinical ovarian tumor model. [2021]Epithelial ovarian cancer is an aggressive malignancy, with a low 5-year median survival. Continued improvement on the development of more effective therapies depends in part on the availability of adequate preclinical models for in vivo testing of treatment efficacy. Mucin 1 (MUC1) glycoprotein is a tumor-associated antigen overexpressed in ovarian cancer cells, making it a potential target for immune therapy. To create a preclinical mouse model for MUC1-positive ovarian tumors, we generated triple transgenic (Tg) mice that heterozygously express human MUC1(+/-) as a transgene, and carry the conditional K-rasG12D oncoallele (loxP-Stop-loxP-K-ras(G12D/+)) and the floxed Pten gene (Pten/(loxP/loxP)). Injection of Cre recombinase-encoding adenovirus (AdCre) in the ovarian bursa of triple (MUC1KrasPten) Tg mice triggers ovarian tumors that, in analogy to human ovarian cancer, express strongly elevated MUC1 levels. The tumors metastasize loco-regionally and are accompanied by high serum MUC1, closely mimicking the human disease. Compared with the KrasPten mice with tumors, the MUC1KrasPten mice show increased loco-regional metastasis and augmented accumulation of CD4+Foxp3+ immune-suppressive regulatory T cells. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells (DC1) loaded with a MUC1 peptide (DC1-MUC1) can circumvent tumor-mediated immune suppression in the host, activate multiple immune effector genes and effectively prolong survival. Our studies report the first human MUC1-expressing, orthotopic ovarian tumor model, reveal novel MUC1 functions in ovarian cancer biology and demonstrate its suitability as a target for immune-based therapies.
Cytotoxic T lymphocytes derived from bone marrow mononuclear cells of multiple myeloma patients recognize an underglycosylated form of MUC1 mucin. [2019]MUC1 is a highly immunogenic epithelial mucin and serves as a tumor-associated antigen in breast, pancreatic and ovarian carcinomas. We previously reported the expression of MUC1 on myeloma cells and the establishment of an HLA-unrestricted cytotoxic T lymphocyte (CTL) line TN that recognized MUC1 from peripheral blood mononuclear cells in a multiple myeloma patient. In this study, we attempted to induce such CTL from six other multiple myeloma patients consecutively in order to show that the induction of the CTL line TN had not resulted from some idiosyncrasy of the first patient. Bone marrow mononuclear cells were used to induce CTL, because they contain myeloma cells that might stimulate the autologous lymphocytes. Bulk CTL lines were induced from two out of six patients. The CTL line TS was CD8+ cell dominant and KY was CD4+ cell dominant. Both CTL lines lysed MUC1+ myeloma and breast carcinoma cell lines. The cytotoxicity of the CTL lines was inhibited by anti-CD3, anti-alpha beta TCR and anti-MUC1 mAb. It was also inhibited by a MUC1 transfectant, but not by a mock transfectant in cold target inhibition assays. MUC1 was transfected into a human colonic carcinoma cell line. The reactivity of anti-MUC1 core protein mAb and the cytotoxicity of the CTL against the transfectant was enhanced by the treatment of the cells with an O-glycosylation inhibitor. Thus it is generally accepted that the HLA-unrestricted CTL which directly recognize the underglycosylated from of MUC1 using their TCR could be induced from a certain proportion (approximately 30%) of untreated multiple myeloma patients.
Long-term intravenous administration of activated autologous lymphocytes for cancer patients does not induce antinuclear antibody and rheumatoid factor. [2017]The treatment of activated autologous lymphocyte can lead to a potent antitumor effect with destruction of autologous cancer cells, but potential adverse autoimmune effects due to destruction of autologous tissue must also be considered. This study was performed to evaluate whether administration of activated autologous lymphocytes induces autoimmune disease. Patients with advanced cancer, who underwent transfer therapy with activated autologous lymphocytes, were eligible for the study. Informed consent was obtained from 22 patients with hepatocelluler carcinoma, ovarian cancer, gastric cancer, etc. The variation in activated lymphocyte phenotypes was CD3+/HLA-DR+ activated T lymphocytes, 23% to 99%; including CD4+ cells, 4% to 65%; CD8+ cells, 10 to 91%; and CD16+/ICD56+ NK cells, 1% to 59%. Of the 22 patients, levels of antinuclear antibody and/or rheumatoid factor were above normal limits during the study in the following 5 patients: 3 patients showed no marked changes, one patient a slight decrease in rheumatoid factor and one patient a slight increase in antinuclear antibody during the course of treatment, respectively. The values for these markers of the other 17 patients varied within normal limits during treatment. Mild transient fever occurred in several patients as an adverse event. There were no other adverse reactions. No clinical symptoms or signs suggestive of autoimmune disease occurred in any patient during or after treatment. These results suggested that long-term administration of activated autologous lymphocytes does not induce autoimmune disease.
T cell suppression as a mechanism for tolerance to MUC1 antigen in MUC1 transgenic mice. [2019]C57BL/6 mice transgenic for human MUC1 (MUC1.Tg) have been developed to study immunologic responsiveness to the human MUC1 tumor-associated antigen. In the present studies, MUC1.Tg mice were immunized with purified human MUC1 antigen and irradiated MUC1-positive (MC38/MUC1) tumor cells. Immunization with MUC1 antigen was associated with induction of an anti-MUC1 antibody response and no detectable cytotoxic T cell reactivity. Similar findings were obtained after immunization with irradiated MC38/MUC1 tumor cells. The results also demonstrate that immunization of MUC1.Tg mice with MUC1 is associated with decreased levels of CD8+ T cells. In addition, expression of alphabeta T cell receptors and CD28 were down-regulated on CD8+ T cells as a consequence of MUC1 immunization. These findings support a role for T cell suppression in tolerance to MUC1 antigen in MUC1.Tg mice.
MUC1-specific cytotoxic T lymphocytes in cancer therapy: induction and challenge. [2021]MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed, in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials.
Expression of MUC1 in primary and metastatic human epithelial ovarian cancer and its therapeutic significance. [2022]MUC1 is associated with cellular transformation and tumorigenicity and is considered as an important tumor-associated antigen (TAA) for cancer therapy. The objective of this study was to evaluate the patterns of MUC1 expression in primary tumors and metastatic lesions in the advanced stages of epithelial ovarian cancers (EOCs) and correlate the expression with clinicopathological features.
Tumor infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival. [2022]Reactivation of tumor infiltrating T lymphocytes (TILs) with immune checkpoint inhibitors or co-stimulators has proven to be an effective anti-cancer strategy for a broad range of malignancies. However, epithelial ovarian cancer (EOC) remains largely refractory to current T cell-targeting immunotherapeutics. Therefore, identification of novel immune checkpoint targets and biomarkers with prognostic value for EOC is warranted. Combining multicolor immunofluorescent staining's with single cell RNA-sequencing analysis, we here identified a TIM-3/CXCL13-positive tissue-resident memory (CD8/CD103-positive) T cell (Trm) population in EOC. Analysis of a cohort of ~175 patients with high-grade serous EOC revealed TIM-3-positive Trm were significantly associated with improved patient survival. As CXCL13-positive CD8-positive T cells have been strongly linked to patient response to anti-PD1 immune checkpoint blockade, combinatorial TIM-3 and PD-1 blockade therapy may be of interest for the (re)activation of anti-cancer immunity in EOC.