Pushing ahead with next-generation vaccines

In 1973, using an electron microscope to study glass-adhering mouse splenocytes (white blood cells that reside in the spleen), Ralph Steinman and Zanvil Cohn discovered an unusual-looking population of cells with an unprecedented ability to activate naive T cells. Choosing to call them “dendritic cells” because of their tree-like formation, these cells are now known as the primary instigators of adaptive immunity and form the basis for a type of immunotherapy known as dendritic cell therapy.

But what exactly is dendritic cell therapy and how much promise does it hold for disease treatment?

What is dendritic cell therapy?

As key sentinel cells, dendritic cells reside throughout the body, particularly in lymphoid organs and at the interface between the body and the environment, such as the skin and linings of the nose, meaning they are constantly exposed to foreign proteins and pathogens. They can also be found in the blood. 

Once activated, dendritic cells migrate to the lymph nodes, where they interact with T cells and B cells to initiate and shape the adaptive immune response. In addition to their role in activating naive T cells, they are thought to play a critical role in guiding the differentiation of regulatory T cells, as well as the development of T cell tolerance. 

Dendritic cell therapy for cancer

Because of the critical role that dendritic cells play in priming anti-tumor T cell immunity, they have long been seen as a major therapeutic target for cancer immunotherapy. This is where dendritic cell therapy comes into play; it is essentially a form of cell therapy that enlists a patient’s own dendritic cells to fight cancer. 

“Typically, these dendritic cells are manufactured from the patient’s peripheral blood mononuclear cells (PBMCs), then ‘trained’ to recognize tumor antigens by loading them with tumor-derived material (often lysate or mRNA),” explained Jay Hartenbach, president and chief operating officer (COO) of Diakonos Oncology, a biotech working on dendritic cell technology.  “Once administered to the patient, these activated dendritic cells help stimulate the patient’s T cells to identify and attack cancer cells expressing those antigens.”

Hartenbach said that, in principle, dendritic cell therapy can target almost any type of cancer, so long as there is an accessible tumor sample to prepare the antigen source. Additionally, unlike other types of immunotherapy such as immune checkpoint inhibitors, dendritic cell therapy can orchestrate a complete response instead of simply blocking or modifying downstream immune signals. It is also highly specific to tumor cells, which not only enhances its efficacy but also reduces potential systemic side effects, giving it an impressive safety profile. 

FDA-approved dendritic cell therapies

However, after decades of research, Provenge (sipuleucel-T) is the only approved dendritic cell-based immunotherapy, after it was given the green light by the  U.S. Food and Drug Administration (FDA) in 2010 for the treatment of metastatic prostate cancer. 

Despite the early success of Provenge and the generally accepted safety of conventional dendritic cell-based cancer vaccines, their clinical implications have generally been unsuccessful, with only 5–15% of patients benefiting from an objective immune response. The limited efficacy of these vaccines is thought to be due to the tumor microenvironment (TME), which often suppresses immune responses and helps tumor cells to evade immune detection. This has also long been an issue for other types of cancer vaccines too, forcing researchers to search outside the box for better solutions in vaccine technology.

Dendritic cell therapy in clinical trials

Current dendritic cell therapy development efforts, therefore, have focused on actively exploring ways to enhance the efficacy of these vaccines by engineering the cells to better target specific cancers and overcome the immunosuppressive factors of the TME. There are currently a few notable companies advancing forms of dendritic cell therapies. 

Diakonos Oncology: Making strides with dendritic cell therapy platform DOC1021

Diakonos Oncology is currently running and expanding a series of clinical trials leveraging its dendritic cell therapy platform, DOC1021, across multiple indications. At the core of this platform is a “double-loading” technique that makes Diakonos stand out in the dendritic cell therapy space.

Instead of loading dendritic cells with either tumor lysate or mRNA – most dendritic cell vaccines have one or the other – Diakonos’ candidate double loads tumor antigens with both lysate and mRNA, in a design that more closely mimics a viral infection. According to Hartenbach, this approach has demonstrated up to an 11x increase in T cell cytotoxicity. 

The double-loading technique was initially brought forward by Will Decker, Diakonos’ chief scientific officer (CSO), after he discovered that dendritic cells detect and initiate Th1 immunity against viral threats after they confirm matching antigens on MHC Class 1 (mRNA), and 2 (lysate). Leveraging this discovery, Decker developed a new dendritic cell vaccine that loads a patient’s cancer antigens onto MHC Class 1 and 2, which subsequently produces a powerful and natural immune response targeting a patient’s cancer.

Hartenbach said that DOC1021 has shown efficacy in treating 10 different cancer types in both clinical and compassionate access programs, in turn demonstrating dendritic cell therapy’s broad potential across both solid and hematologic malignancies.

The candidate is currently being investigated to treat glioblastoma, with a phase 2 trial involving 135 patients set to launch in March 2025 at 20 leading glioblastoma centers across the U.S. This study will build on promising results from an 18-patient phase 1 study that showed an 88% 12-month survival rate, which is a significant improvement on the current standard of care. Additionally, 31% of patients remained alive after a median follow-up of 21 months.

DOC1021 is also being tested to treat pancreatic ductal adenocarcinoma – the most common type of pancreatic cancer – for which it has received fast track designation from the FDA. A phase 1 trial is currently underway at Baylor College of Medicine for 12 patients with advanced pancreatic ductal adenocarcinoma. 

In addition to these two trials, a phase 1 study is set to begin in Q3 2025 investigating DOC1021 in the treatment of refractory melanoma. The trial seeks to determine whether the candidate can help patients with advanced melanoma who have failed standard therapies, such as checkpoint inhibitors or targeted treatments.

According to Hartenbach, Diakonos plans to expand to additional indications in 2026 due to the broad applicability of dendritic cell therapy for tumors.

Northwest Biotherapeutics’ DCVax-L awaiting regulatory approval

Northwest Biotherapeutics’ lead candidate, called DCVax-L, is a lysate-loaded dendritic cell vaccine intended for the treatment of glioblastoma multiforme (GBM), the most lethal form of primary brain cancer. 

The company’s DCVax technology platform uses activated dendritic cells and is designed to target the full set of biomarkers on a patient’s cancer, making it more difficult for tumors to develop “escape variants”, in which they manage to evade the effects of anti-cancer drugs. 

In order to make DCVax for a patient, the patient’s immune cells are obtained through a blood draw. These immune cells are precursors of dendritic cells, called “monocytes.” For DCVax-L, the monocytes are differentiated into dendritic cells and matured, activated, and loaded with antigens from the patient’s own tumor tissue. The dendritic cells are then isolated with very high purity and comprise the DCVax-L personalized vaccine. 

In November 2022, Northwest Biotherapeutics reported positive topline results from its phase 3 trial of DCVax-L that showed both median and long tail survival were increased in both newly diagnosed and recurrent glioblastoma. At the time of these results, the company said that it believed this was the first time in nearly 20 years that a phase 3 trial of a systemic treatment had shown such survival extension in newly diagnosed glioblastoma, and the first time in nearly 30 years that a phase 3 trial of any type of treatment had shown such survival extension in recurrent glioblastoma.

Despite the outcome of the phase 3 study, DCVax-L has still not received regulatory approval. In December 2023, a full year after the results were released, the company finally announced that it had submitted a marketing authorization application to the Medicines and Healthcare Products Regulatory Agency (MHRA) in the U.K. for DCVax-L for glioblastoma brain cancer. 

But, still, another year later, and the company is still awaiting the outcome of its approval application. Reports suggest that the company is still working closely with consultants on matters related to the review, including preparing for upcoming inspections by the MHRA in the U.S. and the U.K. The company is also reportedly struggling for cash and is currently funding itself through a shoestring effort. In December 2024, it announced a $5 million convertible note financing and standby facility for up to $50 million in additional financing. 

Nevertheless, the potential of DCVax-L remains a focal point for investors. And, considering the talks between the company and the MHRA are still ongoing, the candidate could soon receive approval, especially given its positive phase 3 results, as well as the fact that there is a significant need for more treatment options for glioblastoma. 

Mendus’ vididencel vaccine shows promise in phase 2 trial

In November 2020, Immunicum and DCprime merged to form a company that would be a leader in cell-based therapies – specifically in allogeneic dendritic cell therapies. This company, still known as Immunicum, then changed its name to Mendus in 2022. 

Mendus’ lead program, called vididencel, is an off-the-shelf, intradermal vaccine comprising irradiated leukemic-derived dendritic cells from the company’s DCOne cell line that is administered directly into the tumor. This leads to local inflammation in the tumor microenvironment and the triggering of anti-tumor immune responses. It is currently being evaluated as a maintenance therapy in acute myeloid leukemia (AML) and ovarian cancer to reduce or prevent tumor recurrence. 

Vididencel has received fast track designation from the FDA for the treatment of AML, and, in December 2024, Mendus announced that it had presented positive survival data from the ongoing phase 2 trial of vididencel at the ASH 2024 conference, showing that the majority of AML patients treated with vididencel remained alive and disease-free in long-term follow-up, with a median follow-up of 41.8 months.

Furthermore, Mendus also reported positive topline data in December 2024 from its phase 1 clinical trial of vididencel in ovarian cancer. The data collected from all 17 patients treated confirmed that vididencel stimulates immune responses against ovarian cancer antigens, as a potential basis for an effective anti-tumor response. Plus, a strong safety profile for vididencel was also confirmed. 

According to the company, a long-term follow-up of patients treated with vididencel as part of the same trial is ongoing, with the next read-out based on a 2-year follow-up expected to occur in Q4 of 2025.

The future of dendritic cell therapy  

When dendritic cell vaccines first came to the market with the approval of Provenge, they were expected to become one of the most promising approaches against cancer. But, ultimately, it has taken time to overcome the limitations that have held these types of therapies back for many years, and only now are we beginning to see a glimpse of the true potential of dendritic cell therapy. 

Indeed, the global dendritic cell cancer vaccine market size is expected to grow in the coming years, increasing at a compound annual growth rate (CAGR) of 12.18% from 2023 to 2030, after being valued at $593.30 million in 2022. 

According to Grand View Research, the growth of the market is attributed to the increasing overall clinical trial activity related to cancer vaccines, as well as growing demand for mRNA-based vaccines and evolving cancer therapeutics. Furthermore, the rise in the number of cancer patients, increased government funding for the development of cancer vaccines, and advancements in vaccine technology are driving market growth. 

Hartenbach himself believes that if positive results continue with Diakonos’ DOC1021, it is inevitable that dendritic cell therapies will regain popularity in the industry. “Over the past year, Diakonos has seen a surge in interest from both the medical community and academic researchers, reflecting growing recognition of dendritic cell therapy’s unique advantages. We anticipate that ongoing positive clinical results will not only spotlight Diakonos’ but the entire field of dendritic cell-based immunotherapies as well.”

New technologies related to dendritic cell therapy