Dendritic Cell-Based Cancer Vaccines Santos, Patricia M; Butterfield, Lisa H
The Journal of immunology (1950),
01/2018, Letnik:
200, Številka:
2
Journal Article
Recenzirano
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Dendritic cells (DC) are specialized immune cells that play a critical role in promoting an immune response against Ags, which can include foreign pathogenic Ags and self-tumor Ags. DC are capable of ...boosting a memory T cell response but most importantly they are effective initiators of naive T cell responses. Many years of studies have focused on the use of DC vaccines against cancer to initiate and shape an antitumor-specific immune response and/or boost existing spontaneous antitumor T cell responses. In this study we give a brief overview of DC biology, function, and cellular subsets, and review the current status of the field of DC as cancer vaccines.
Cancer vaccines Butterfield, Lisa H
BMJ,
04/2015, Letnik:
350, Številka:
apr22 14
Journal Article, Book Review
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Cancer vaccines are designed to promote tumor specific immune responses, particularly cytotoxic CD8 positive T cells that are specific to tumor antigens. The earliest vaccines, which were developed ...in 1994-95, tested non-mutated, shared tumor associated antigens that had been shown to be immunogenic and capable of inducing clinical responses in a minority of people with late stage cancer. Technological developments in the past few years have enabled the investigation of vaccines that target mutated antigens that are patient specific. Several platforms for cancer vaccination are being tested, including peptides, proteins, antigen presenting cells, tumor cells, and viral vectors. Standard of care treatments, such as surgery and ablation, chemotherapy, and radiotherapy, can also induce antitumor immunity, thereby having cancer vaccine effects. The monitoring of patients’ immune responses at baseline and after standard of care treatment is shedding light on immune biomarkers. Combination therapies are being tested in clinical trials and are likely to be the best approach to improving patient outcomes.
Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed ...pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma.
In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039.
Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3–19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six 14%), decreased lymphocyte count (five 12%), prolonged activated partial thromboplastin time (four 10%), and decreased platelet count (three 7%) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three 7% each). Nine (11%) patients (five 12% in the bone sarcoma group and four 10% in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis.
The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab.
Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.
The clinical successes in cancer immunotherapy have led to a critical need for biomarkers in cancer immunotherapy. It is of the utmost importance to know who is most likely to benefit from these ...therapies (predictive biomarkers) but also who is starting to respond (prognostic biomarkers) and how the therapy functions in order to make rational combination choices (mechanism of action biomarkers). The Society for Immunotherapy of Cancer (SITC) Biomarkers Task Force addressed the state of the art and made a series of recommendations for the field, which is summarized here.
What's next for cancer vaccines Adamik, Juraj; Butterfield, Lisa H
Science translational medicine,
11/2022, Letnik:
14, Številka:
670
Journal Article
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Cancer vaccines have been shown clinically to drive tumor-reactive cell activation, proliferation, and effector function. Unfortunately, tumor eradication by treatment with cancer vaccines has been ...unsuccessful in many patients. Critical steps are under way to improve vaccine efficacy and combine them with immunotherapy and standard-of-care treatments.
Immunotherapy of cancer in 2012 Kirkwood, John M.; Butterfield, Lisa H.; Tarhini, Ahmad A. ...
CA: a cancer journal for clinicians,
September/October 2012, Letnik:
62, Številka:
5
Journal Article
Dendritic cells (DC) have been tested in cancer immunotherapy clinical trials for two decades. Over this time, the methods of DC culture (or manufacture) have evolved, the approaches for antigen ...loading have broadened, the maturation signals have varied and different sites of administration have been tested. The post-vaccination immunologic questions asked have also varied between trials and over time. In this review, I will consider multiple aspects of DC-based vaccines tested in cancer patients, including the cell culture, antigen loading, maturation, and delivery, as well as what we have learned from testing immune responses in vaccinated patients who have benefited clinically, and those who have not measurably benefited.
We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ...ipilimumab) and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses) bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b), IIIC (32; N2c, N3), IV (2). Worst toxicities included Grade 3 diarrhea/colitis (5; 14%), hepatitis (2; 6%), rash (1; 3%), elevated lipase (3; 9%). Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS) was 11 months, 95% CI (6.2-19.2). There was a significant decrease in circulating myeloid derived suppressor cells (MDSC). Greater decrease in circulating monocyte gate MDSC Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associated with improved PFS (p = 0.03). There was a significant increase in circulating regulatory T cells (Treg; CD4⁺CD25hi⁺Foxp3⁺) that, unexpectedly, was associated with improved PFS (HR = 0.57; p = 0.034). Baseline evidence of fully activated type I CD4⁺ and CD8⁺ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens was detected and was significantly potentiated after ipilimumab. In tumor, there was a significant increase in CD8⁺ T cells after ipilimumab (p = 0.02). Ipilimumab induced increased tumor infiltration by fully activated (CD69⁺) CD3⁺/CD4⁺ and CD3⁺/CD8⁺ T cells with evidence of induction/potentiation of memory T cells (CD45RO⁺). The change in Treg observed within the tumor showed an inverse relationship with clinical benefit and greater decrease in tumor MDSC subset Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associated with improved PFS at one year. Neoadjuvant evaluation revealed a significant immunomodulating role for ipilimumab on Treg, MDSC and effector T cells in the circulation and tumor microenvironment that warrants further pursuit in the quest for optimizing melanoma immunotherapy.
A wide variety of tumor antigens have been targeted in cancer immunotherapy studies. Traditionally, the focus has been on commonly overexpressed antigens shared across many patients and/or tumor ...types. As the field has progressed, the identity of human tumor rejection antigens has broadened. Immunologic monitoring of clinical trials has slowly elucidated candidate biomarkers of immune response and clinical response, and conversely, of immune dysfunction and suppression. We have utilized MART-1/Melan-A in our melanoma studies and observed a high frequency of immune responses and several significant clinical responses in patients vaccinated with this melanosomal protein. Alpha-fetoprotein is a shared, overexpressed tumor antigen and secreted glycoprotein that we have tested in hepatocellular cancer vaccines. Our recent studies have identified immunosuppressive and immune-skewing activities of this antigen. The choice of target antigen and its form can have unexpected effects.
Immunomodulatory impact of α-fetoprotein Munson, Paul V.; Adamik, Juraj; Butterfield, Lisa H.
Trends in immunology,
06/2022, Letnik:
43, Številka:
6
Journal Article
Recenzirano
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α-Fetoprotein (AFP) is a fetal glycoprotein produced by most human hepatocellular carcinoma tumors. Research has focused on its immunosuppressive properties in pregnancy, autoimmunity, and cancer, ...and human AFP directly limits the viability and functionality of human natural killer (NK) cells, monocytes, and dendritic cells (DCs). AFP-altered DCs can promote the differentiation of naïve T cells into regulatory T cells. These properties may work to shield tumors from the immune system. Recent efforts to define the molecular characteristics of AFP identified key structural immunoregulatory domains and bioactive roles of AFP-bound ligands in immunomodulation. We propose that a key mechanism of AFP immunomodulation skews DC function through cellular metabolism. Delineating differences between fetal ‘normal’ AFP (nAFP) and tumor-derived AFP (tAFP) has uncovered a novel role for tAFP in altering metabolism via lipid-binding partners.
Cord blood-derived alpha-fetoprotein (AFP) has an incompletely understood role in pregnancy, as well as in autoimmune diseases. AFP is currently being investigated as a potential therapeutic for multiple autoimmune diseases. These diverse biological roles are complicated by earlier approaches that did not account for AFP sources (where a tumor-derived AFP might be more potently immunosuppressive than normal AFP due to differential binding partner molecules.Tumor-derived AFP has broad immunosuppressive effects on multiple cell types, including NK cells, NKT cells, and dendritic cells (DC). The mechanisms of action include AFP protein and non-protein binding partners. AFP can also have indirect effects on lymphocytes after uptake by DCs, as well as after direct uptake by lymphocytes.A key mechanism of AFP-mediated immunosuppression involves the binding of lipid partners which can modulate cellular metabolism. Lipid-AFP complexes can impact DC phenotype, function, and metabolic pathway utilization. Some of these lipids have been identified as polyunsaturated fatty acids which can preferentially bind AFP.
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