Dendritic Cell-based Cancer Vaccines
Renato Brito Baleeiro, Ph.D
Principal Scientist | Immuno-oncology | Cancer Vaccines and Immunotherapy | Drug Discovery | Project Leader | R&D
Dendritic cells (DCs), discovered by Ralph Steinman in 1973, revolutionized our understanding of immune responses. Steinman's groundbreaking work led to the Nobel Prize in Physiology or Medicine in 2011, highlighting the significance of DCs in immunology. Since then, extensive research has illuminated the critical role of DCs in both health and disease, particularly in cancer immunotherapy.
Dendritic Cells Biology
DCs serve as professional antigen-presenting cells (APCs), acting as a crucial link between the innate and adaptive immune systems. They specialize in capturing and presenting antigens to T cells, thereby initiating and regulating immune responses. DCs are characterized by their ability to present antigens on major histocompatibility complex (MHC) molecules to T cells, facilitating their activation and differentiation into effector cells.
DCs exhibit remarkable heterogeneity, comprising various subsets with distinct phenotypic and functional properties. Classical or conventional DCs (cDCs) include type 1 cDCs (cDC1s) and type 2 cDCs (cDC2s), along with plasmacytoid DCs (pDCs). Each subset plays unique roles in immune surveillance and response. While cDC1s excel in cross-presentation and CD8+ T cell activation, cDC2s primarily engage in presenting exogenous antigens to CD4+ T cells. pDCs, on the other hand, specialize in producing type I interferons, essential for antiviral defense.
The classification of DC subsets has evolved over time, driven by advances in high-dimensional flow cytometry and single-cell transcriptomics. Initially categorized based on functional and location-based criteria, DC classification has transitioned towards lineage-based distinctions. Emerging evidence suggests distinct developmental origins for cDCs and pDCs, further refining our understanding of DC heterogeneity.
Identifying specific surface markers has facilitated the characterization of DC subsets. For instance, cDC1s can be distinguished by markers such as CADM1, CD141, and XCR1, while cDC2s exhibit greater heterogeneity, often requiring additional markers for precise identification. These markers enable researchers to isolate and study distinct DC populations, unraveling their unique roles in immune regulation.
Functional heterogeneity is another hallmark of DC subsets, with each subset contributing to various aspects of immune responses. While cDC1s are crucial for priming cytotoxic CD8+ T cell responses, cDC2s specialize in CD4+ T cell activation. pDCs, meanwhile, play a pivotal role in antiviral immunity through their robust type I interferon production. Understanding these functional differences is essential for harnessing DCs' immunotherapeutic potential.
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Dendritic Cells and Cancer
In cancer immunotherapy, DCs have emerged as promising therapeutic targets due to their ability to initiate and modulate immune responses against tumors. DC-based vaccines, aimed at eliciting tumor-specific immune responses, have garnered significant interest in both preclinical and clinical settings. These vaccines typically involve ex vivo manipulation of DCs, where they are loaded with tumor antigens and matured to enhance their immunogenicity before reinfusion into patients.
Despite promising results, the clinical efficacy of DC-based vaccines remains limited, partly due to immunosuppressive mechanisms within the tumor microenvironment (TME). Strategies to overcome these challenges include combining DC vaccination with immune checkpoint blockade or adoptive T cell transfer. Such multimodal approaches hold promise for enhancing antitumor immune responses and improving patient outcomes.
Recent preclinical studies have showcased various advancements in DC vaccination strategies. These include the use of specific adjuvants to enhance DC activation, genetic modifications to augment immunogenicity, and novel combinations with immune-modulating agents. Additionally, insights from murine models have provided valuable understanding of DC biology and their interactions within the TME.
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Summary of Clinical Studies on DC-Based Vaccines for Cancer Therapy
Since February 2019, 25 peer-reviewed research papers or clinical studies have been published, reporting on the safety and efficacy of dendritic cell (DC)-based vaccines for treating various cancers. These studies cover 13 different cancer types, with melanoma, glioblastoma (GBM)/glioma, prostate cancer, ovarian cancer, and pancreatic cancer being the most common. The majority of these studies evaluated autologous DCs pulsed with tumor-associated antigens (TAAs) or TAA-derived peptides, with some studies focusing on TAA-coding RNAs, autologous cancer cell lysates, or adenovirus-transfected DC vaccines. Notably, Phase I or I/II studies predominated, assessing the safety and potential adverse effects of DC vaccination regimens, which were generally well tolerated, with mild-to-moderate adverse effects reported in a small subset of patients. Immunogenicity induced by DC vaccines was consistently observed, with increased antigen-specific T- or B-cell activity and/or lymphocyte tumor infiltration noted in many studies.
Among the studies focused on specific TAAs, melanoma antigen family (MAGE) peptides, glycoprotein 100 (gp100), and tyrosinase were commonly targeted, predominantly in melanoma patients. However, some studies explored personalized neoantigens. DC vaccination was evaluated either as a single adjuvant therapy or in combination with conventional anticancer therapies such as chemotherapeutics or immunotherapeutic agents like immune checkpoint inhibitors (ICBs) or immunomodulatory monoclonal antibodies. Notably, combination therapies with ICBs, particularly anti-PD1 or anti-CTLA4 antibodies, were frequently investigated.
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Several Phase III trials are ongoing, particularly in GBM, testing TAA-loaded DC vaccines or combinations with cytokine-induced killer cells. In these trials, the most common therapeutic approach to DC vaccination involves autologous DCs pulsed with TAAs or TAA-derived peptides, tumor lysate, or TAA-coding RNA. To enhance efficacy, DC vaccination is being combined with other cancer therapies such as chemo- and radiotherapy, adoptive cell transfer, recombinant cytokines, or targeted therapies.
Status Update on Clinical Trials
A total of 55 clinical trials evaluating DC-based vaccines against cancer were registered between February 2019 and December 2021. GBM was the most common cancer type being targeted, followed by basket trials enrolling patients with various solid tumors. Ongoing trials predominantly focus on Phase I or II studies, with a few Phase III trials in advanced stages. Most therapeutic approaches involve autologous DCs pulsed with TAAs or TAA-derived peptides, tumor lysate, or TAA-coding RNA. Some trials are exploring personalized neoantigens. To improve immunogenicity and efficacy, DC vaccination is being combined with other cancer therapies, particularly ICBs, chemotherapy, or adoptive cell transfer.
First DC-based Vaccine Approved by the FDA for Prostate Cancer
Sipuleucel-T, marketed as Provenge, is a cell-based immunotherapy developed by Dendreon Pharmaceuticals, LLC, specifically tailored for metastatic, asymptomatic, or minimally symptomatic castrate-resistant prostate cancer (mCRPC), also known as hormone-refractory prostate cancer (HRPC). This advanced stage of prostate cancer, indicated by lymph node involvement and distant tumors, poses significant challenges in treatment, often leading to a lethal outcome.
The treatment process involves three main steps:
To minimize side effects, premedication with acetaminophen and antihistamines is recommended.
Common side effects of sipuleucel-T include bladder pain, swelling, bloody or cloudy urine, body aches, chest pain, chills, confusion, diarrhea, difficulty breathing or speaking, double vision, and sleep disturbances.
Sipuleucel-T received approval from the U.S. Food and Drug Administration (FDA) in 2010 for the treatment of asymptomatic or minimally symptomatic mCRPC. It was subsequently included in the National Comprehensive Cancer Network (NCCN) Compendium as a "category 1" treatment recommendation for HRPC, influencing reimbursement decisions by Medicare and major healthcare insurance providers.
Clinical trials, including D9901, D9902a, and IMPACT, have demonstrated the overall survival benefit of sipuleucel-T in patients with mCRPC. The IMPACT trial, which formed the basis for FDA approval, showed a median survival time of 25.8 months for sipuleucel-T-treated patients compared to 21.7 months for placebo-treated patients, with a statistically significant increase in overall survival.
Ongoing research includes the PROTECT trial, which evaluates the efficacy of sipuleucel-T in patients whose prostate cancer is still controlled by hormone treatment or surgical castration after primary treatment failure. Another trial investigates the combination therapy of sipuleucel-T with ipilimumab (Yervoy) in patients with advanced prostate cancer, assessing safety and anti-cancer effects.
In summary, sipuleucel-T represents a significant advancement in the treatment of mCRPC, offering improved overall survival and a potential therapeutic option for patients at an advanced stage of prostate cancer. Ongoing research continues to explore its efficacy in combination therapies and in patients with different disease statuses, aiming to further enhance treatment outcomes and quality of life.
Concluding Remarks
While there has been some decline in the number of published and ongoing clinical trials on DC-based vaccination for cancer therapy, interest remains high, especially in niche applications like GBM. DC vaccines offer potential in combination with other therapies, particularly in ICB-resistant tumor landscapes. However, challenges remain, including the need for clear survival advantages in clinical trials, addressing resistance pathways, reducing manufacturing costs, and identifying robust patient pre-selection biomarkers. Despite these challenges, DC vaccines hold promise in sensitizing tumors and overcoming ICB non-responsiveness in various cancer types and patients, with ongoing research focusing on engineering better vaccines and increasing personalization.