The Future of Cancer Vaccines: Beyond TLR9 Agonists


The development of efficacious cancer vaccines represents a cornerstone of contemporary oncology. While the established prophylactic vaccines against human papillomavirus (HPV) and hepatitis B virus (HBV) have demonstrably reduced cancer incidence, therapeutic cancer vaccines for established tumors remain an elusive goal. Toll-like receptor 9 (TLR9) agonists have emerged as a promising class of immunotherapeutic agents, stimulating anti-tumor immune responses through activation of the innate immune system. However, limitations associated with TLR9-based strategies necessitate exploration of alternative approaches for the next generation of cancer vaccines.

Challenges and Limitations of TLR9 Agonism

TLR9 agonists, such as CpG oligodeoxynucleotides (CpG-ODNs), elicit potent activation of antigen-presenting cells (APCs), promoting the maturation of dendritic cells and subsequent priming of T lymphocytes. This immunostimulatory effect translates to enhanced tumor recognition and destruction. However, several challenges have limited the widespread clinical adoption of TLR9 agonists:

  • Off-target effects: TLR9 signaling can trigger systemic inflammation, leading to dose-limiting toxicities.
  • Limited antigen specificty: TLR9 agonists activate the innate immune system in a non-antigen-specific manner, potentially compromising the focus of the immune response.
  • Inefficient delivery: Effective delivery of TLR9 agonists to APCs within the tumor microenvironment remains a challenge.

Emerging Technologies for Next-Generation Cancer Vaccines

To overcome the limitations of TLR9 agonists, researchers are exploring innovative platforms for cancer vaccine development:

  • Viral vectors: Engineered viral vectors can be employed for targeted delivery of tumor-associated antigens (TAAs) and co-stimulatory molecules, promoting potent and specific anti-tumor T cell responses.

How vectors work to transfer genetic material

  • Dendritic cell vaccines: Ex vivo manipulation of dendritic cells with TAAs and adjuvants can generate potent antigen-specific T cell immunity. 

Overview of Dendritic cell (dys)functions in cancer. Upon detection of tumor antigens and danger signals, dendritic cells (DCs) become activated, upregulate co-stimulatory surface molecules and secrete pro-inflammatory cytokines. Mature DCs can (cross)-present antigens, trigger tumor-specific T cell responses, and stimulate natural killer (NK) cell activity to unleash cytotoxic anti-tumor immunity (left). During tumor development and progression, the release of tumor-derived suppressive factors prevents DC progenitors from properly differentiating ①, and differentiated DCs from fulfilling their functions ②. Resulting immature, tolerogenic and/or dysfunctional DCs, characterized by the expression of TGF-b, IL-10, IDO-1, PGE2, and PD-L1, can inhibit T cell anti-tumor responses ③. Furthermore, they can differentiate into and favor the expansion of immunosuppressive populations such as myeloid-derived suppressor cells (MDSCs), BDCA1+CD14+ cells, and tumor-associated macrophages (TAMs). Overall, the impairment of DCs is a crucial step for tumor immune evasion, triggering a cascade of immunosuppression that hampers anti-tumor immunity and creates a propitious environment for tumor growth and metastasis initiation.

  • Nanoparticles: Nanoparticle-based delivery systems can enhance the bioavailability and intratumoral targeting of TAAs and adjuvants, promoting localized immune activation.

TEM (a, b, and c) images of prepared mesoporous silica nanoparticles with mean outer diameter: (a) 20nm, (b) 45nm, and (c) 80nm. SEM (d) image corresponding to (b). The insets are a high magnification of mesoporous silica particle.

  • Oncolytic viruses: Viruses engineered to selectively replicate within and lyse tumor cells can serve as in situ vaccines, releasing TAAs and stimulating anti-tumor immunity.

Intratumoural (IT) injection of viruses as a strategy to enhance cancer vaccination. (a) IT injection of non-replicating viruses expressing cytokines and/or costimulatory molecules can be used to influence the immune environment within the tumour to improve antigen processing and presentation. (b) Oncolytic viruses are potently immunogenic, many being based on vaccine virus strains. The direct injection of oncolytic viruses into tumours has been used with the aim of stimulating an anticancer immune response while also causing direct cellular cytotoxicity. (c) Oncolytic viruses expressing cytokines, often termed oncolytic vaccines, have also been investigated extensively, and have demonstrated activity in a variety of tumours when injected directly into the tumour mass. (d) The observation that tumours often exhibit an immunosuppressive phenotype, that limits attack by the immune system, is leading the development of new virus strains that encode inhibitors of key immunosuppressive pathways and networks.

  • Pioneering TLR9 Agonist Vaccines: Companies like Oligovax, a subsidiary of the Gentaur Group, are at the forefront of developing next-generation cancer vaccines leveraging TLR9 agonists. Their lead candidate, Litenimod, demonstrates promise in stimulating a targeted and robust immune response against cancer cells. This exemplifies the exciting potential of TLR9 agonists in the future of cancer immunotherapy. (Oligovax Website:

Optimizing the Immune Response

Beyond novel delivery platforms, researchers are exploring strategies to optimize the immune response elicited by cancer vaccines:

  • Combination immunotherapy: Combining cancer vaccines with immune checkpoint inhibitors or other immunomodulatory agents holds promise for overcoming immunosuppressive mechanisms within the tumor microenvironment.
  • Personalized vaccines: Tailoring cancer vaccines to the unique mutational landscape of individual tumors using neoantigen targeting offers the potential for highly personalized and effective immunotherapy. 


The future of cancer vaccines lies in the exploration of innovative platforms that surpass the limitations of TLR9 agonists. By harnessing the potential of viral vectors, dendritic cell manipulation, nanoparticles, and oncolytic viruses, alongside optimized delivery strategies and combination immunotherapy approaches, researchers aim to develop the next generation of safe and efficacious cancer vaccines.

Learn more about how cancer vaccines work in this video:


The Future of Cancer Vaccines: Beyond TLR9 Agonists
Gen store May 24, 2024
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