Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment

Abstract

Dendritic cells (DCs) are essential in immunity owing to their role in activating T cells, thereby promoting antitumor responses. Tumor cells, however, hijack the immune system, causing T cell exhaustion and DC dysfunction. Tumor-induced T cell exhaustion may be reversed through immune checkpoint blockade (ICB); however, this treatment fails to show clinical benefit in many patients. While ICB serves to reverse T cell exhaustion, DCs are still necessary to prime, activate, and direct the T cells to target tumor cells. In this review we provide a brief overview of DC function, describe mechanisms by which DC functions are disrupted by the tumor microenvironment, and highlight recent developments in DC cancer vaccines.

Keywords: cancer; dendritic cells; immune suppression; immunotherapy; tumor microenvironment; vaccines.

Fig 1. DC dysfunction in the tumor microenvironment

The tumor microenvironment is enriched in immune suppressive elements that serve to promote tumor growth by directly or indirectly inhibiting DC functions. These elements include suppressive cytokines, suppressive alarmins, hypoxia, metabolic stress and evasive mechanisms like antigen masking. Cumulatively these elements impair multiple aspects of DC functions and result in absence of adequate Th1 differentiation in the tumor microenvironment.

Fig 2. Variables in DC vaccine platform

A summary of current aspects of DC vaccine pipeline undergoing optimization. A) Differentiating immature DCs from precursors: patient derived monocytes and CD34⁺ Hematopoietic stem cells could be used to generate MoDCs or XCR1⁺Clec9a⁺ DCs or CD1d DCs or Langerhan cells, respectively. Or natural/conventional DCs could be directly isolated from patient blood. In future perhaps DC like cell lines could be optimized for generating a universal immature DC line. B) Maturing DCs: DCs would be matured using cytokines, TLR ligands, PGE₂, CD40 ligand or a combination of above. Maturation signals can be provided as exogenous stimuli or transfected/transduced into the immature DCs as in the case of Trimix DCs and SMART DCs. C) Selecting and loading antigens: Whole tumor lysates or tumor cell fusion with DCs may be used. TAAs or neo-antigens (personalized or shared) may be selected. Antigens are loaded on DCs in form of short or long peptides through traditional DC priming, as DNA through lentiviral transduction or in RNA form through electroporation. Antigens could be introduced with CLRs, mannose receptors, CD40L or CD40 activating antibodies to improve cross-presentation. D) Combinations: To maximize DC vaccine clinical efficacy the vaccine should be administered with most suitable adjuvant in combination with, i) CTLA4 or PD1/PDL1 inhibitor, ii) inhibitors of immune suppression, iii) facilitators of DC mobilization like Td toxoid vaccine, GM-CSF or Flt3L, iv) other cell based therapies like CIK, ACT and CAR T cell therapy and v) in combination with standard chemotherapy and radiation therapy. MoDCs: Monocyte derived DCs; nDCs: natural DCs; PGE₂: prostaglandin E2; TAAs: Tumor associated antigens; CLR: C type lectin receptors.

Fig 3. Two-arm approach for treating cancer with anti-tumor DC targeted vaccines

A “two-arm” approach enables DC vaccines to overcome tumor-induced immune-suppression and successfully induce anti-tumor immunity. Under “ARM-1” of this approach patients would first undergo tumor de-bulking by undergoing surgery and/or followed by radiation/chemotherapy. Thereafter, patients would be treated with checkpoint blockade inhibitors to reverse T cell exhaustion. At the same time other T cell inhibitory elements like regulatory T cells and myeloid derived suppressor cells (MDSCs) would need to be neutralized by use of drugs such as cyclophosphamide or anti-CD25 antibodies, or agents that modify the TME e.g. IDO inhibitors, adenosine antagonists etc. Under ARM-2, the patient would be pre-conditioned with adjuvants and with agents like Flt3L to mobilize DCs before being vaccinated with autologous DCs loaded with shared or personalized antigens. At this stage other immunotherapies such as adoptive T cell transfer, CAR T cell therapy, insitu tumor vaccination with TLR ligands and Oncolytic virus therapy could also be co-administered to boost the efficacy of DC vaccines.