Dendritic Cell Vaccines in Cancer Treatment

Introduction to Dendritic Cell Vaccines

The dendritic cell (DC) vaccine, a new type of immunotherapy, has received wide attention in incurable diseases with immune dysfunction, especially cancer. The DC vaccine enhances tumor-specific antigens’ uptake, processing, and presentation, thereby boosting the antitumor immune destruction. Over the past two decades, a series of DC vaccine-based tumor treatments have entered clinical trials, and some have been approved for marketing.

Antitumor Mechanisms of Dendritic Cell Vaccines

Immune evasion is one of the hallmarks of cancer, which results from the reduced recognition of the body’s immune system. Tumors have developed multiple pathways to impair DC function and inhibit antitumor T cell immunity, constituting a vital premise for tumor growth and metastasis. In this regard, the DC vaccine is designed for remodeling tumors' DC functions with the following mechanisms.

Providing Adequate Mature Dendritic Cells in Tumors

Taking up the damage-associated molecular patterns (DAMPs) from dying tumor cells, DCs undergo maturation and accumulate in tumor tissues, preparing for initiating and maintaining antitumor T cell immunity.

However, tumors have also acquired the ability to suppress DC maturation. Hypoxic tumor cells resulting from overgrowth produce prostaglandin E2 (PGE2) which inhibits the immune-stimulatory activity of DAMPs on macrophages and DCs in vitro. The vascular endothelial growth factor (VEGF) released by tumor cells also affects DC differentiation and maturation.

Additionally, DCs’ viability is potentially reduced by PGE2 through impairing NK cells, which have been proven to promote intratumoral DC survival by producing Fms-like tyrosine kinase 3 ligand (FLT3L).

Having been incubated with tumor-specific antigens and stimulating factors for 48 hours or more in vitro, the DC vaccines have matured and can resist tumorous discouragement.

Enhancing HLA-I Presentation in Tumors

Following maturation, DCs load antigens on class I human leukocyte antigen (HLA-I) for CD8+ T cell priming. To escape from the response of CD8+ T cell, tumors alternate the DCs’ function to prime T cells and the antigen presentation pathway. In addition to DCs’ dysfunction, the genetic expression of HLA-I is reduced. With functional DCs and enough HLA-I, DC vaccines rescue the weak antigen presentation in tumor tissues.

Avoiding Antigen Depletion

If a specific recognized antigen is dispensable for tumor cells’ survival, like a by-product of tumorigenesis, antigen depletion can occur by copy number loss at the genomic level. CD8+ T cells’ killing of the entire cell population can also induce antigen loss. Every DC in a DC vaccine has loaded cancer antigens on HLA-I for presentation in vitro, avoiding the expression downregulation in the tumor microenvironment.

Dendritic Cell Vaccine in Clinic

Approved Dendritic Cell Vaccines

Table 1. Basic information of approved DC vaccines.

DCVax®-L for Glioblastoma

On July 16, 2007, the first DC vaccine, DCVax-L, was approved by the Swiss Institute of Public Health for post-operative treatment of glioblastoma. According to a placebo-control phase 3 clinical trial, in newly diagnosed glioblastoma, patients (n = 331) have overall survival (OS) of 23.1 months past the surgery date, while 223 patients with DCVax-L lived ≥ 30 months past their surgery date, among whom 182 patients lived ≥ 36 months with a Kaplan-Meier (KM)-derived mOS of 88.2 months, suggesting an extension in survival. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event (NCT00045968).

Provenge® (Sipuleucel-T) for Prostate Cancer

Sipuleucel-T, the first approved DC vaccine and a therapeutic prostate cancer vaccine, has been clinically applied in advanced castration-resistant prostate cancer.

On April 29, 2010, Sipuleucel-T was approved by the United States Food and Drug Administration (FDA) and has shown evidence of reducing the risk of death in male patients with metastatic castration-resistant prostate cancer (mCPRC). There are also several clinical trials of it. In a double-blind and placebo-controlled phase 3 trial, the Sipuleucel-T group (n = 341) showed a relative reduction of 22% in the risk of death as compared with the placebo group (n = 171) (hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; p = .03 < .05). There is a 4.1-month improvement in median survival (25.8 months in the Sipuleucel-T group versus 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the Sipuleucel-T group versus 23.0% in the placebo group (NCT00065442).

In addition, the combined treatment of ipilimumab and Sipuleucel-T was tolerated with no unexpected adverse events and induced a more significant T cell activation (NCT01804465).

As the only approved DC vaccine by the FDA, Sipuleucel-T stands at the center of DC vaccine research with 42 related clinical trials. Due to space limitations, this review only introduces the main results from published articles.

Vaccell® for Pancreatic Adenocarcinoma

On December 12, 2013, Vaccell® received approval as Japan’s first cell immunotherapy drug for pancreatic ductal adenocarcinoma (PDA) patients. In 49 patients with inoperable and advanced pancreatic carcinoma, the median survival time (MST) of the patients receiving LAK cells was significantly longer. Overall survival ranged from 57 to 975 days, giving an MST of 360 days.

Dendritic Cell Vaccines in Clinical Trials

According to the U.S. library of medicine, there are 160 ongoing clinical trials of DC vaccines, most of which come from America. Melanoma, prostate cancer, and glioblastoma are the top 3 attentional areas. In this section, trials with results are introduced, and studies with the same drugs are posted, except for the approved ones. Besides, some scientists hope to use DC vaccines to end the spread of COVID-19. Related clinical trials are completed and recruiting, but their results have not been posted.

CMV-DCs for Glioblastoma

Human cytomegalovirus (CMV) antigens have been identified in gliblastoma but not in normal brains, providing a target antigen for DC vaccines. Patients who received CMV-DC vaccination (n = 17) experienced a significant increase in CMV-specific CD8+ T cells (NCT00693095). Other clinical trials see in Table 2.

Table 2. Clinical trials for CMV-DCs.

TLPLDC for Melanoma

In a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine for maintenance therapy in patients with resected stage III/IV melanoma, the per treatment (PT) analysis of the vaccine group showed improved 24-month disease-free survival (DFS) (62.9% versus 34.8%, p = 0.041) (NCT02301611). Other clinical trials see in Table 3.

Table 3. Clinical trials for TLPLDC.

MelCancerVac for Metastatic Colorectal Cancer

Treatment with MelCancerVac was non-toxic, and clinical response was achieved in 24% of the patients. The patients maintained a high quality of life during treatment (NCT00311272). Other clinical trials see in Table 4.

Table 4. Clinical trials for MelCancerVac.

AGS-003 (Rocapuldencel-T) for Renal Cell Carcinoma

A phase III trial compared the safety and efficacy of a combination therapy dosing regimen of Rocapuldencel-T plus sunitinib in patients with metastatic renal cell carcinoma (mRCC) (NCT01582672). However, the combination therapy did not improve OS in patients. Other clinical trials see in Table 5.

Table 5. Clinical trials for AGS-003.

AV-COVID-19

The approved COVID-19 vaccines, which all focus on activating B cells’ immune response, fail to supply persistent protection with a decline in antibodies several months after vaccination. T cell-oriented vaccines like DC vaccines are probably promising for effective and long-lasting immunity. Other clinical trials see in Table 6.

Table 6. Clinical trials for AV-COVID-19.

Conclusion

Traditional vaccines offer protection through the production of antibodies from B cells, while DC vaccines focus on activating functional T cells, which are crucial in tumor elimination. DC vaccines can effectively repair the DC defect in tumors’ immune evasion, making it a breakthrough in tumor therapy. In addition, DC vaccines are a promising strategy to end our war against COVID-19. However, the complex preparation and high price may be the biggest limitation of clinical application and wide commercialization.

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