MUC1 Vaccine Research Articles

Efficacy and Safety of MUC1 Antigen-Specific Vaccine as a Breakthrough Solution in the Treatment of Advanced Non-Small Cell Lung Cancer

Introduction: Non-Small Cell Lung Cancer (NSCLC) is the leading cause of death for cancer patients globally. Most of the patients are diagnosed in advanced stage that can only receive conventional chemotherapy with low overall survival and low progression-free survival outcomes. With the advancement of technology, researchers have discovered that antigen-specific vaccine could be utilized to fight tumor cells. MUC1 antigen-specific vaccine is a novel solution that has been proved to be specific and accurate against NSCLC. In this study, we would like to present current best evidences regarding the efficacy and safety of MUC1 antigen specific vaccine in battling NSCLC. Methods: Literature search was conducted on databases, namely PubMed, Scopus, Cochrane, Science Direct, EBSCOhost, and Google Scholar up to August 27th 2022. Our inclusion criteria include randomized controlled trials in patients with advanced stage NSCLC, given MUC1 antigen-specific vaccine as treatment, compared to placebo as control group, and measured the efficacy in terms of overall survival and progression-free survival, quality of life, and adverse events. Results and discussion: Six randomized controlled trials were included in this review. Overall, longer overall survival and progression-free survival is observed in all studies. However, significance differed from study to study. This could be attributed to different patient characteristics and chemotherapy regimens used. MUC1 antigen-specific vaccine is more effective in patients who received concurrent chemoradiotherapy, high sMUC1 and ANA level, and non-squamous tumor type. Minimum adverse events were reported and incidence is similar with the control group. No negative impact on quality of life was observed. Conclusion: MUC1 vaccine showed a promising impact on improving patients’ overall survival and progression-free survival while ensuring patient’s safety. However, further studies with larger sample size are recommended on more specific populations, for instance, patients with concurrent chemotherapy.

Addition of the MUC-1 vaccine tecemotide to neoadjuvant systemic therapy for patients with early breast cancer: Survival results from the prospective randomized ABCSG 34 trial.

Addition of the MUC-1 vaccine tecemotide to neoadjuvant systemic therapy for patients with early breast cancer: Survival results from the prospective randomized ABCSG 34 trial.

Pre-vaccination transcriptomic profiles of immune responders to the MUC1 peptide vaccine for colon cancer prevention.

Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-κB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness.

Abstract 6537: Single cell transcriptomics uncovers cellular and molecular differences in PBMCs of responders and non-responders to the MUC1 cancer vaccine given in the preventative setting

Abstract Introduction: A single arm trial (NCT007773097) and a double-blind, placebo controlled randomized trial (NCT02134925) were conducted in patients with newly diagnosed advanced colonic adenomas to test the safety and immunogenicity of the MUC1 antigen vaccine and its potential to prevent new adenoma formation. These are the first trials of a non-viral cancer vaccine administered in the absence of cancer. In both trials, the vaccine was safe and strongly immunogenic in 43% and 25% of participants (Responders), respectively. The lack of robust response in a significant number of participants suggested, for the first time, that even in a premalignant setting, the immune system may have already been exposed to regulatory influences that, in the case of the vaccine, determine who does and who does not respond. We hypothesized that there could be molecular and cellular differences in the immune competence between vaccine responders and non-responders, and that they could be identified by studying their pre-vaccination peripheral blood mononuclear cells (PBMCs). Methods: The two MUC1 vaccine trials are described in https://doi.org/10.1101/2022.10.05.22280474 and https://doi.org/10.1158%2F1940-6207.CAPR-12-0275. We performed single cell RNA-sequencing (scRNAseq) on banked pre-vaccination PBMCs from 16 Responders and 16 Non-Responders, determined by anti-MUC1 IgG response. Using differential gene expression (DGE), pathway enrichment, and network estimation analyses, we identified specific cell types, genes, and pathways that differ between responders and non-responders. Results: Pre-vaccination PBMCs from Responders contained a significantly higher percentage of CD4+ naive T cells, while Non-Responders showed significantly higher percentage of CD8+ T effector memory (TEM) cells and a higher percentage of CD16+ monocytes. DGE and gene interaction network analysis showed a higher level of expression of T cell activation genes, such as Fos and Jun, in the CD4+ naive T cells in Responders. Further network analysis showed that these genes were directly connected to response. We also found pre-vaccination specific gene ontology (GO) pathways for translational and transcriptional activity enriched in all cell types in Responders compared to Non-Responders. Conclusion: Our analyses identified candidate biomarkers that are predictive of a preventative cancer vaccine response. Thus, our results can be used for patient selection for vaccine administration. Furthermore, we identified cell type differences and transcriptional pathways that provide information of possible mechanisms of vaccine response. Citation Format: Daniel Y. Yuan, Michelle L. McKeague, Matthew T. Dracz, Olivera J. Finn, Panayiotis V. Benos. Single cell transcriptomics uncovers cellular and molecular differences in PBMCs of responders and non-responders to the MUC1 cancer vaccine given in the preventative setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6537.

Abstract PR002: A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer

Abstract Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. An emerging area of interest for risk reduction is immunoprevention. MUC1 glycoprotein is aberrantly expressed in adenocarcinomas, including lung cancer and their premalignant lesions. MUC1 vaccine in the premalignant or high-risk setting may be effective in halting neoplastic development and progression. Trial design: Through the NCI-funded Cancer Prevention Network (CPN), we conducted a two-center pilot trial to evaluate immunogenicity of the MUC1 vaccine (assessed at 12 weeks), and safety (assessed at up to 24 weeks) in current and former heavy smokers. 87 participants were screened in order to have at least 40 evaluable for baseline and 12-week immunogenicity assessments. Smoking history of ≥30 pack-years and either current (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria were standard for lung cancer screening. Methods: MUC1 peptide plus polyICLC adjuvant (Hiltonol) vaccine was given at week 0, 2 and 10. Blood was collected for safety tests and immune assays pre and 2 weeks post each vaccine, and at week 24. Anti-MUC1 IgG titer was evaluated by ELISA. Based on previous studies of this vaccine, 40 evaluable participants would provide 96% power to detect immune response rate of 15% versus 40%, using a 2-sided test of proportions with type I error rate of 0.05. PBMC were assayed for the presence of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) (secondary endpoint). Circulating levels of inflammatory cytokines and hsCRP were evaluated using commercially available tests (exploratory endpoint). AEs and toxicities were monitored for up to 24 weeks from the first vaccine. Results: 87 individuals were screened and 50 registered. 45 completed the study, 26 current and 19 former smokers (time since last smoked: average 7.8 years; 11 months -13 years). The vaccine was well-tolerated with injection site reactions being the most common AE. Immune response to the vaccine was lower than expected, with 2 current and 2 former smokers developing anti-MUC1 IgG titers ≥2 fold higher at week 12 over baseline (10%). We found high circulating levels of MDSCs in PBMC of both current and former smokers and very low or no serum cytokines. Conclusions: A preventative vaccine trial was feasible in individuals at high risk for lung cancer. However, we discovered a high level of immune suppression, previously documented only in advanced lung cancer. Mitigating the development of lung cancer in heavy smokers through vaccine administration may be limited by related immunosuppression. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Samantha Fatis, John McKolanis, Jia Xue, Pamela Beatty, Camille Jacqueline, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Liz S. Ambulay, Nathan Foster, Ryan McMurray, Carrie Strand, Andres M. Salazar, Lisa Bengtson, Eva Szabo, Paul Limburg, Malgorzata Wojtowicz, David E. Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR002.

MUC1 vaccines using β-cyclodextrin grafted chitosan (CS-g-CD) as carrier via host-guest interaction elicit robust immune responses

We construct MUC1 vaccines using β-cyclodextrin grafted chitosan (CS-g-CD) as carrier via host-guest interaction. These vaccines based on non-covalent assembling can provoke robust immune responses, including high level of specific antibodies and cytokines. The induced antibodies can specifically recognize tumor cells and mediate cytotoxicity against tumor cells. These results indicate that CS-g-CD with strong immunostimulatory activities can be a straightforward platform for peptide-based vaccine construction.

Abstract SY17-03: Tumor-associated antigen MUC1 vaccine for colon cancer prevention

Abstract For most human cancers, infectious etiology is unknown and preventative vaccines based on viral antigens, such as HPV for cervical cancer, are not a possibility. However, non-viral cancer-associated antigens, self-antigens abnormally expressed on tumors, have been identified as candidates for vaccines. In patients diagnosed with cancer, preexisting immunity to some of these antigens correlates with better disease outcome or reduced risk of recurrence. In transgenic mice or other animal models where they are expressed as self-antigens, immune responses induced to their tumor forms protect from tumor challenge without causing autoimmunity. Therapeutic vaccines that have utilized these antigens have had only marginal efficacy, which extensive research has now attributed to the presence of many immunosuppressive influences in the tumor microenvironment. MUC1 is one such antigen that has been shown effective as a vaccine in preclinical animal models but has had limited immunogenicity and little efficacy as a therapeutic vaccine in numerous clinical trials in many epithelial tumors, including cancer. Hypothesizing that the major difference between the outcome of the vaccine in preclinical models and in clinical trials is likely to be the high level of immune suppression in cancer patients, we began to develop models and MUC1 vaccines for cancer prevention in patients at risk, before immune suppression develops. We determined first that the tumor form of MUC1 was expressed on early premalignant lesions as well and chose premalignant colonic polyps as the first setting for testing the preventative vaccine. Data will be reviewed from a published feasibility study confirming immunogenicity and safety of the MUC1 vaccine in healthy individuals at risk for colon cancer. Data will then be presented from a recently completed unpublished randomized, double blind placebo controlled multi-center prophylactic MUC1 vaccine trial in the same patient population, those with a history of advanced colonic polyps and therefore at increased risk of developing colon cancer. Citation Format: Olivera (Olja) J. Finn. Tumor-associated antigen MUC1 vaccine for colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY17-03.

Meeting Proceedings of the 2nd Annual Immuno-Oncology Society of India Conference (I-OSICON-2020), Mumbai, India.

Meeting Proceedings of the 2nd Annual Immuno-Oncology Society of India Conference (I-OSICON-2020), Mumbai, India.

Alum colloid encapsulated inside β-glucan particles enhance humoral and CTL immune responses of MUC1 vaccine

We have developed a MUC1 antigen-based antitumor vaccine loaded on alum colloid encapsulated inside β-glucan particles (GP-Al). The constructed vaccine induced strong MUC1 antigen specific IgG antibody titers and enhanced CD8+ T cells cytotoxic effect to kill tumor cells. These results indicated that GP-Al can be served as an efficient delivery system and adjuvant for the development of cancer vaccines especially small molecule antigens based cancer vaccines.

Indomethacin enhances anti-tumor efficacy of a MUC1 peptide vaccine against breast cancer in MUC1 transgenic mice.

In recent years, vaccines against tumor antigens have shown potential for combating invasive cancers, including primary tumors and metastatic lesions. This is particularly pertinent for breast cancer, which is the second-leading cause of cancer-related death in women. MUC1 is a glycoprotein that is normally expressed on glandular epithelium, but is overexpressed and under-glycosylated in most human cancers, including the majority of breast cancers. This under-glycosylation exposes the MUC1 protein core on the tumor-associated form of the protein. We have previously shown that a vaccine consisting of MUC1 core peptides stimulates a tumor-specific immune response. However, this immune response is dampened by the immunosuppressive microenvironment within breast tumors. Thus, in the present study, we investigated the effectiveness of MUC1 vaccination in combination with four different drugs that inhibit different components of the COX pathway: indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inhibitor), and AH6809 (prostaglandin E2 receptor antagonist). These treatment regimens were explored for the treatment of orthotopic MUC1-expressing breast tumors in mice transgenic for human MUC1. We found that the combination of vaccine and indomethacin resulted in a significant reduction in tumor burden. Indomethacin did not increase tumor-specific immune responses over vaccine alone, but rather appeared to reduce the proliferation and increase apoptosis of tumor cells, thus rendering them susceptible to immune cell killing.

Abstract CT236: Randomized, double-blind, placebo-controlled trial of preventative MUC1 vaccine in patients with newly diagnosed advanced adenomas: Results from one-year booster

Abstract Background: Immunoprevention via targeting antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a less invasive prevention strategy than endoscopic surveillance. Specificity of the immune response and long-term memory provide the potential for prolonged protection. Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a double-blind randomized trial in individuals with a diagnosis of advanced colorectal adenomas within the previous year. We are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC as an adjuvant, for its immunogenicity, ability to elicit immune memory and prevent recurrence of colorectal adenomas. Aims: We previously reported on the vaccine immunogenicity at week 12 (vaccine administered at 0, 2, and 10 weeks) compared to placebo. Here we report the ability of the vaccine to elicit long-term memory by measuring increase in anti-MUC1 antibody levels following a booster administered at one year. Methods: Subjects with endoscopically resected advanced adenoma (defined as ≥1cm, tubululovillous or villous histology, or with high grade dysplasia) were randomized. The primary endpoint was the response to the vaccine at week 12 assessed by monitoring anti-MUC1 IgG antibody titer ratio defined as t12/t0, where t0 was the titer pre-vaccination, and t12 was the titer at week 12. The key secondary endpoint was to assess anti-MUC1 IgG response at week 55 to a booster at week 52 in the vaccine arm compared to placebo. Results: 102 eligible subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. The mean age was 59.4±7.0 (range 40-70), 60.8% male, 88.2% white, and 18.6% Hispanic or Latino ethnicity. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of individuals receiving vaccine (ratio range -0.5-17.3), vs. 0/50 in placebo group (2-sided p=.0001), and was ≥1.5 in 19/52 (36.5%) individuals receiving vaccine compared to 1/50 (2%) in placebo group (P<.0001). To evaluate immune memory, 1-year booster data available for 95 patients (51-MUC1, 44-placebo) were analyzed. 10/13 (76.9%) of the week 12 vs. week 0 vaccine responders showed a response at week 52 vs. baseline and 11/13 (84.6%) at week 55 vs. week 52. Using an IgG ratio of 2 (per-protocol), the response rate was 33% for MUC1 vs. 5% for placebo (1-sided p=0.0003). Using a ratio of 1.5 yielded similar results (37% MUC1 vs. 9% Placebo (1-sided p=0.0008). The MUC1 arm had significantly higher IgG at week 52 (1-sided p=0.0294), week 55 (1-sided p=0.0048), and significantly higher week 55 to week 52 IgG ratio values (1-sided p=0.0293). Conclusions: Subjects with a recent history of advanced adenoma receiving a MUC1 vaccine compared with a placebo were significantly more likely to develop an immune response at week 12, confirming the vaccine’s immunogenicity, and to respond again at week 55 to a booster injection on week 52, confirming the vaccine’s ability to elicit immune memory. Follow-up colonoscopy to evaluate the vaccine’s potential to lower adenomatous polyp recurrence rates are in progress. Citation Format: Olivera J. Finn, Lisa Boardman, Marcia Cruz-Correa, Ajay Bansal, David Kastenberg, Chin Hurr, Sharon Kaufman, Colleen Akerley, Lynda Dzubinski, April Felt, Karrie Fursa, L.M. Rodriguez, Ellen Richmond, Asad Umar, Eva Szabo, John McKolanis, Ryan McMurray, Nathan Foster, Andres Salazar, Paul Limburg, Robert Schoen. Randomized, double-blind, placebo-controlled trial of preventative MUC1 vaccine in patients with newly diagnosed advanced adenomas: Results from one-year booster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT236.

Abstract CT222: A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer

Abstract Background: Smoking is the most common etiology for lung cancer. Smoking cessation, even when successful, does not eliminate risk of lung cancer. With inconsistent results of lung chemoprevention trials, an emerging area of interest is immunoprevention, in particular vaccines. MUC1 is a transmembrane glycoprotein aberrantly overexpressed in adenocarcinomas, including lung cancer. Abnormal MUC1 expression is also characteristic of premalignant lesions, including bronchial dysplasia and atypical adenomatous hyperplasia. This suggests that immunization with a MUC1 vaccine in the premalignant or high-risk setting, before the tumor and cytotoxic therapy could suppress the immune system, might be effective in inducing strong immunity and reducing cancer risk. Trial design: Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a two-center pilot trial to evaluate co-primary endpoints: immunogenicity of the MUC1 peptide plus polyICLC adjuvant vaccine (assessed at 12 weeks) and safety (assessed at up to 24 weeks) in current and former smokers who are at high risk for lung cancer. 50 participants will be screened in order to have 40 evaluable participants for baseline and 12-week immunogenicity assessments. Eligibility: Smoking history of ≥30 pack-years and either current smoker (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria are standard. Immunogenicity and safety: MUC1 peptide plus polyICLC adjuvant vaccine will be administered at week 0, 2 and 10. The primary endpoint is anti-MUC1 IgG titer that is ≥2 fold higher at week 12 compared to baseline. Based on previous studies of this vaccine, we expect that 40 evaluable participants will provide 96% power to detect immunogenicity response rate of 15% versus 40% using a 2-sided test of proportions with type I error rate of 0.05. AEs and toxicities will be monitored for up to 24 weeks from the first vaccine. Secondary Objectives: We will explore differences, if any, in vaccine immunogenicity in current vs. former smokers. Smoking induces chronic inflammation (hallmark of cancer) associated with immunosuppression. We will evaluate pre-vaccination levels of circulating myeloid derived suppressor cells (MDSC) and correlate with the response to the vaccine. We will explore the impact, if any, of this vaccine on the markers of inflammation (hsCRP, IL-6) and the effect of baseline levels of these markers on the ability to successfully vaccinate. We will also assess the relationship between COPD status and immune response in current versus former smokers. The trial is open to accrual. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Lisa Bengtson, John McKolanis, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Nathan Foster, Andres Salazar, Malgorzata Wojtowicz, Eva Szabo, Paul Limburg, David Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT222.

Circulating Myeloid Derived Suppressor Cells (MDSC) That Accumulate in Premalignancy Share Phenotypic and Functional Characteristics With MDSC in Cancer.

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate in circulation of cancer patients and at tumor sites where they suppress anti-tumor immunity. We previously reported that in a colon cancer prevention trial of a MUC1 vaccine tested in individuals at increased risk for colon cancer, those who did not mount immune response to the vaccine had higher pre-vaccination levels of circulating MDSC compared to those who did. We also reported that individuals with pancreatic premalignancy, Intraductal Papillary Mucinous Neoplasm (IPMN), had increased circulating levels of MDSC that inversely correlated with spontaneous antibody responses against the pancreatic tumor associated antigen MUC1, abnormally expressed on IPMN. Accumulation of MDSC in cancer and their immunosuppressive role had been well established but their presence in premalignancy was unexpected. In this study we compared MDSC in premalignancy with those in cancer with the hypothesis that there might be differences in the composition of various MDSC subpopulations and their immunosuppressive functions due to different lengths of exposure to disease and/or different tissue microenvironments. In cohorts of patients with premalignant polyps, colon cancer, premalignant IPMN, and pancreatic cancer, we confirmed higher levels of MDSC in premalignancy compared to healthy controls, higher levels of MDSC in cancer compared to premalignancy, but no difference in their subpopulation composition or immunosuppressive capacity. We show that levels of MDSC in premalignancy correlate negatively in vivo with spontaneous MUC1-specific antibody responses and in vitro with polyclonal T cell proliferation and IFN-γ secretion.

Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T-cell therapy in patients with third line or greater TNBC.

e12566 Background: Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer that is frequently aggressive and has limited treatment options. We hypothesize that effective and sustained response against TNBC requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low dose chemotherapy, SBRT, off-the-shelf cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with previously-treated metastatic TNBC was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA, MUC1, brachyury, and HER2 vaccines, yeast vector-based Ras, brachyury and CEA vaccines, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 8 subjects with 3rd-line or greater TNBC have received at least 3 treatment cycles (mean = 6 cycles). All treatment was administered in an outpatient setting. All subjects had at least 1 grade ≥3 TRAE, primarily chemotherapy-related neutropenia. Grade ≥3 haNK-related AEs (fever and fatigue) were observed in 2 subjects. 2 subjects experienced SAEs. 7 subjects remain alive, with 6 subjects receiving ongoing study treatment. 1 CR (confirmed) and 2 PRs (one confirmed) have been observed to date. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting with a manageable safety profile. Clinical trial information: NCT03387085.

Liposomal Fc Domain Conjugated to a Cancer Vaccine Enhances Both Humoral and Cellular Immunity.

Targeted delivery of antigens to antigen-presenting cells (APCs) by utilizing natural anticarbohydrate antibodies is a promising approach for selective uptake and enhanced antigen presentation. Previously, we reported that in the presence of a natural antibody, anti-rhamnose antibody (anti-Rha), the bacterial sugar rhamnose conjugated with liposomal cancer antigen MUC1-Tn enhances antigen presentation by APCs such as dendritic cells by targeting Fc gamma receptors. The idea was to utilize the natural human anti-Rha antibodies present in human serum for targeted delivery of cancer-specific antigens. Recently, we found that the IgG3 antibody isotype was the most prevalent anti-Rha antibody generated in mice immunized with rhamnose-Ficoll (Rha-Ficoll) antigen. In this manuscript, we have conjugated the murine IgG3-Fc with a MUC1-containing cancer vaccine and compared the humoral and cellular immune response to this vaccine with one targeted via the human anti-Rha antibody and to the MUC1 vaccine alone. This Fc approach enhanced antibody production and T-cell proliferation almost to the same level as using the anti-Rha antibody. These results suggest that targeting Fc directly to dendritic cells can be an alternative approach to human anti-Rha for generating effective antigen-primed T-cells.

β-Glucan as an immune activator and a carrier in the construction of a synthetic MUC1 vaccine.

We describe the preparation of a cancer vaccine candidate by conjugating a MUC1 peptide antigen to the β-glucan polysaccharide, which serves both as a carrier and an immune activator. In contrast to amorphous polysaccharides, peptide-β-glucan conjugates form uniform nanoparticles that facilitate the delivery of antigens and binding to myeloid cells, thus leading to the activation of both innate and adaptive immunity.

Abstract LB-305: Randomized, double-blind, placebo-controlled immunoprevention trial with MUC1 vaccine in patients with newly diagnosed advanced adenomas

Abstract Background: Immunotherapy targeting tumor-associated antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a relatively non-invasive and non-toxic prevention strategy, and because of the specificity of the immune response and its long-term memory, the potential for prolonged protection. In a double-blind randomized trial in patients with a diagnosis of advanced colorectal adenomas within the previous year, we are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC (Hiltonol®) as an adjuvant, for its immunogenicity and effect on colorectal adenoma recurrence at follow up colonoscopy. Aim: We report on a primary endpoint, MUC1 immunogenicity at week 12 (following vaccine or placebo administration at 0, 2, and 10 weeks), and on determinants of the immune response and vaccine toxicity. Methods: Subjects with an advanced adenoma (defined as ≥1cm, tubulovillous or villous histology, or with HGD) were randomized. Response to the vaccine was assessed by monitoring IgG anti-MUC1 antibody titer ratio; defined as t12/t0, where t0 is the initial titer measured prior to vaccination, and t12 is the titer drawn at 12 weeks. A ratio of 2.0 was used as the primary definition of a significant immune response. T Regulatory and myleoid derived suppressor cell (MDSC) levels at baseline were assessed in relation to vaccine response. Adverse events (AEs) were recorded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results: 102 subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. Subjects had a mean age of 59.4±7.0 (range 40-70) years, 60.8% were male, 88.2% were white, and 18.6% Hispanic or Latino. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of patients receiving vaccine (ratio range 2.9-17.3), vs. 0/50 in placebo group (P=.0001), and was ≥1.5 in 19/52 (36.5%) of patients receiving vaccine compared to 1/50 (2%) in placebo group (P<.0001). In the vaccinated group, the IgG ratio was ≥2.0 in 45% of women (9/20) vs. 12.5% of men (4/32) (P=0.009) and ≥1.5 in 55% of women (11/20) vs. 25% of men (8/32) (P=0.03). In the vaccinated group, reduced levels of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) pre-vaccination were associated with response, 0.2±0.1 among responders (n=13) vs. 0.8±1.1 among non-responders (N=39) (p=0.0006) whereas monocytic MDSC and T regulatory cells (CD4+CD25, Foxp3) were not. There were no grade 3 adverse events (AE) possibly or probably related to the vaccine. The most common AE was an injection site reaction (grade 1 or 2) which occurred in 80.8% (n=42/52) in vaccine group vs. 6.0% in the placebo group (3/50). Conclusions: Subjects with an advanced adenoma receiving MUC1 vaccine compared with a placebo are significantly more likely to develop an anti-IgG MUC1 immune response at 12 weeks. Women and subjects with lower circulating PMN-MDSC levels at baseline were more likely to respond. The vaccine was well tolerated. Follow up for the effect of the vaccine on adenomatous polyp recurrence is ongoing. Citation Format: Robert E. Schoen, Lisa A. Boardman, Marcia Cruz-Correa, Ajay Bansal, Pamela L. Beatty, David Kastenberg, Chin Hur, Lynda Dzubinski, Luz Rodriguez, Andres Salazar, John McKolanis, Drew Seisler, Nathan R. Foster, May-Yin Polley, Paul J. Limburg, Olivera J. Finn. Randomized, double-blind, placebo-controlled immunoprevention trial with MUC1 vaccine in patients with newly diagnosed advanced adenomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-305.

Soluble PD-1-based vaccine targeting MUC1 VNTR and survivin improves anti-tumor effect

Soluble PD-1 (sPD1) can bind with ligands PD-L1/PD-L2 on the surface of dendritic cells (DCs). Therefore, a sPD1 vaccine fused with an immunogen can increase T cell activation against cancer. Here, we constructed a MUC1 and survivin (MS) combination gene tumor vaccine expressing MS fused with soluble PD-1 (sPD1/MS). To investigate whether the sPD1/MS fusion vaccine could enhance tumor-specific immune responses, its immunogenicity and anti-tumor activity were examined after intramuscular immunization in mice. Compared with the MS DNA vaccine, the specific cytolysis rate of the sPD1/MS fusion DNA vaccine was increased from 21.64% to 34.77%. Moreover, the sPD1/MS vaccine increased the tumor suppression rate from 17.18% to 30.96% and prolonged survival from 6.96% to 19.44% in a murine colorectal cancer model. Combining the sPD1/MS vaccine with oxaliplatin improved the tumor suppression rate to 74.71% in the murine colorectal cancer model. The sPD1/MS vaccine could also exert a good anti-tumor effect, increasing the tumor infiltrated CD8+ T cells by 6.5-fold (from 0.10% to 0.65%) in the murine lung cancer model. In conclusion, the sPD1/MS vaccine showed good immunogenicity and anti-tumor effect by activating lymphocytes effectively.

Mo1987 - Randomized, Double-Blind, Placebo-Controlled Immunoprevention Trial with MUC1 Vaccine in Patients with Newly Diagnosed Advanced Adenomas

Mo1987 - Randomized, Double-Blind, Placebo-Controlled Immunoprevention Trial with MUC1 Vaccine in Patients with Newly Diagnosed Advanced Adenomas

Myeloid derived suppressor cells (MDSC) and anti-MUC1 immunosurveillance in pre-malignancy and cancer

Abstract Recent work from our lab showed that in a colon cancer prevention trial of a tumor antigen MUC1 vaccine in patients with premalignant colon adenomas, those who did not make anti-MUC1 IgG, had higher pre-vaccination levels of circulating MDSC compared to vaccine responders. This was the first observation of increased MDSC in premalignancy. MDSC in premalignancy have not been compared to MDSC in cancer and our hypothesis is that there might be differences in the composition of various MDSC subpopulation and their immunosuppressive functions due to the shorter time of exposure to disease and differences in the disease microenvironment. We are testing this hypothesis on two cohorts of patient samples, premalignant and malignant colon and pancreas. In both cohorts we saw an increase in MDSC in premalignant and malignant disease over healthy controls. The colon premalignant group could be divided into MDSChighAnti-MUC1 IgGlow and MDSClowAnti-MUC1 IgGhigh confirming our previous observations that MDSC are impeding anti-MUC1 immune response in premalignancy as well therefore potentially facilitating progression to cancer. The pancreas cohort also showed increase in MDSC in patients with pancreatic cysts (IPMN), precursors to pancreatic cancer, as well as their suppression of anti-tumor immunity. Furthermore, we found increased levels of PGE2 and its metabolite in patients’ serum from both cohorts, which is closely related to MDSC proliferation and mechanism of suppression. While we do not see much difference in the MDSC phenotype and subpopulation composition, the immunosuppressive capacity of tumor MDSC appears to be greater. We are currently testing this observation in vitro in T cell suppression assays.