Immunotherapeutic strategies and clinical trials of Dendritic cells
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P215-217
2025-12-07
52
The immune system can distinguish self from non-self and eliminate intruding or transformed material from the body. The advancement in the understanding of innate and adaptive immune responses and their regulation has enabled targeted strategies mobilizing the immune system to combat immunopathology. In recent years, immunotherapy has revolutionized the treatment of diseases, in particular cancer. An important type of immunotherapy is DC vaccination (Fig. 1). Numerous clinical trials conducted over the last two decades have established the safety and feasibility of DC vaccines aimed to generate immune responses against infectious pathogens, for example, HIV, and various tumor antigens. Despite eliciting and strengthening antigen-specific immune responses, DC vaccination as monotherapy yields suboptimal clinical outcome. For example, the use of Sipuleucel-T, the first DC-based cancer vaccine approved by the US Food and Drug Administration (FDA), for the treatment of metastatic castration-resistant prostate cancer prolonged median sur vival time by 4.1 months compared to the placebo-treated patients. In general, objective response rates with DC-based cancer vaccines rarely exceed 15%. Similarly, according to a recent meta-analysis of 12 clinical trials, the overall success rate of DC vaccination for the treatment of HIV, defined as partial or at least transient viral load decrease, was estimated to be 38.2%. The suboptimal clinical performance of DC vaccines highlights the need to understand the DC biology better and improve the design of therapeutic DC-based strategies.
Fig1. DENDRITIC CELL-BASED CANCER VACCINES. Summary of some of the DC-based cancer vaccination strategies being used in clinical trials to induce antitumor adaptive immune responses. Tumor antigens can be loaded onto ex vivo generated DCs and administered to the patients alone or in conjunction with adjuvants. An alternative to ex vivo production of DC vaccines is in situ vaccination, in which the vaccine is generated in vivo. Combining DC-based cancer vaccines with different immunomodulatory treatments might provide therapeutic synergism. Flt3L, Fms-like tyrosine kinase receptor 3 ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; mRNA, messenger RNA; PGE2, prostaglandin E2; Poly-ICLC, polyinosinic-polycytidylic acid poly-L-lysine carboxymethylcellulose; TLR, Toll-like receptor.
DCs comprise a small fraction of blood cells. Therefore, the generation of sufficient DC numbers for vaccination strategies may be challenging. Various ex vivo protocols have been developed to generate patient-derived autologous DC subsets, for example, moDCs, cDCs, or pDCs, from distinct sources, such as peripheral blood monocytes or CD34+ precursor cells mobilized from the bone marrow. Isolation techniques used to obtain the source population, as well as the culture method utilized to expand DCs, influence the phenotype, function, and potency of ex vivo generated DCs. Due to the ease of ex vivo expansion protocols and their availability, moDCs have been most frequently used for the preparation of DC vaccines. However, as each DC subset is unique in their antigen presentation capacity and role in disease settings, the adaption of ex vivo culture systems that allow generation and expansion of different DC subsets (cDC1, cDC2, and pDC) to clinical settings will be key to improve the efficacy of DC vaccines. Several studies evaluating the efficacy of pDC and cDC-based cancer vaccines are already underway.
Antigen selection and antigen delivery are two key factors that con tribute to the success of DC-based therapies. DC vaccines are intended to promote strong antigen-specific adaptive immunity. Therefore, the immunogenic potential of the targeted antigens impacts the magnitude of elicited immune responses. To date, most DC vaccines are prepared by loading autologous DCs with microbial or tumor anti gens ex vivo prior to reinfusion into patients. Various antigen sources can be utilized to load DCs ex vivo: (1) synthetic peptides; (2) whole tumor lysates (e.g., NCT03803397 and NCT03990493 by PrimeVax); (3) DC-tumor cell fusions, hybrid cells that act as DCs and express complete tumor antigens; (4) electroporation with mRNA encoding antigens; and (5) transduction with viral vectors encoding antigens. An alternative to ex vivo production of DC vac cines is in situ vaccination, in which the vaccine is generated in vivo. This strategy eliminates the need for ex vivo cell manipulation, thereby simplifying the vaccine production pipelines. Agents utilized to form in situ DC vaccines include (1) antibodies binding to DC-specific cell surface molecules, such as Clec9A, Clec12A, Mannose receptor, DEC-205 and CD40 (e.g., NCT03358719, NCT02166905, NCT02376699, NCT02482168, NCT00648102, NCT00709462, and NCT01103635) that can mediate antigen delivery to DCs; (2) viral vectors encoding antigens; (3) oncolytic viruses, which induce tumor cell death, thereby releasing tumor antigens; (4) nanoparticles,; (5) DC-activating agents; (6) modified RNA or DNA vaccines (NCT02410733); and (7) GM-CSF-transduced tumor cells (GVAX platform). Other platforms that combine ex vivo and in situ DC-based vaccination approaches have also been developed and tested in mouse models, such as the extracellular vesicle internalizing receptor (EVIR) platform, in which DCs are transduced with a chimeric receptor encoding lentivirus ex vivo that enables the selective uptake of tumor-derived EV in vivo. Talimogene laher-parepvec (T-VEC), a modified herpes simplex virus, is a first-in-class FDA-approved oncolytic in situ vaccine. T-VEC selectively replicates in tumor cells and lyses them, which release viral progeny and tumor antigens. Additionally, T-VEC expresses GM-CSF and promotes DC function. FDA approved the use of T-VEC in patients with unresectable melanoma after a 16.3% durable response rate in patients receiving intralesional T-VEC versus 2.1% in patients receiving sub cutaneous GM-CSF, as well as a 4.4-months prolonged median survival time in the T-VEC group.
Another important factor impacting the potency of DC-based vaccinations is the method for DC activation. Various strategies mentioned previously for antigen loading to DCs can also be utilized for introducing DC-activating agents. DCs may be activated by TLR ligands, such as TLR3 agonist Poly-ICLC, TLR4 agonist LPS, TLR7 agonist imiquimod, TLR7 and TLR8 agonist resiquimod, and TLR9 agonist CpG DNA. Pro-inflammatory cytokines, such as IFN-I, IL-1β, IL-6, TNF, and PGE2 , can also be used to activate DCs. In addition, DCs can be engineered to express multiple immunostimulatory molecules. For example, the Trimix DCs express constitutively active TLR-4, as well as CD40-L and CD70. Alternatively, expression of inhibitory molecules, such as PD-L1 and PD-L2, by DCs can be silenced, for example, by using siRNA (NCT02528682). Intratumoral (IT) injection of DC-activating agents can lead to in situ activation of DCs. For example, IT administration of TLR9 agonist CpG oligonucleotide PF-3512676, together with low-dose radiation, in patients with low-grade B-cell lymphoma induced tumor-specific CD8+ T cells and led to complete or partial responses in a subset of patients. Other immune modulators such as Poly-ICLC and STING agonists have also been tested as inducers of in situ DC activation. Moreover, stimulating local inflammation, e.g., by administering potent recall antigens or Flt3L, is another strategy to enhance the efficacy of DCs. To enhance the elicited immunity, multiple agents can be incorporated into the design of the DC vaccine. For example, a recent phase II trial tested a regimen of Flt3L treatment together with Poly-ICLC and a vaccine comprising anti DEC-205-NY-ESO-1 in high-risk melanoma patients, where Flt3L administration was randomized. Findings demonstrated that the addition of Flt3L enhanced the immunogenicity of the DC vaccine and induced potent and durable immune responses.
The superior efficacy and clinical relevance of combination therapies over monotherapies, by therapeutic synergism while retaining safety profiles, have been demonstrated in many contexts. Accordingly, to unleash the full power of DC-based therapies, com bination strategies with different immunomodulatory treatments, for example, chemotherapy, radiotherapy, and checkpoint blockade, have been studied. In addition to eliminating malignant calls and lowering tumor burden, chemotherapy, and radiotherapy-triggered tumor cell death releases tumor antigens and induces exposure of immunogenic molecules on tumor cells, which facilitate DC antigen uptake and activation. Chemotherapy drugs can induce other immunogenic signals that further stimulate DCs. For example, taxane-induced release of cellular ATP potentiates inflammasome activation and IL-1β release, and cyclophosphamide-induced release of tumor nucleic acids can lead to type I IFN secretion. Finally, chemotherapy can deplete immunosuppressive cells at the TME, rendering TME more sensitive to DC vaccine-induced antitumor T cell activity. Checkpoint inhibition (ICI) can also improve the efficacy of DC-based therapies, both by reinvigorating DC-therapy-induced T cells (e.g., anti-PD-1, anti-CTLA-4) and blocking inhibitory molecules expressed by DCs (e.g., anti-PD-L1). In fact, several studies have indicated an enhanced efficacy of DC-therapy upon combination with ICI.
Finally, other factors also influence the success of DC-based treatments, such as the route, dose, and schedule of vaccine administration, as well as the timing of vaccination. Although most DC vaccination trials to date have been conducted in patients with advanced disease, DC-therapy is likely to be most effective in patients with low tumor burden, as early neoadjuvant studies suggest (NCT01431196, NCT03387553). Future controlled studies integrating these key components will improve the efficacy of DC-based therapies both in cancer and infectious disease settings.
الاكثر قراءة في المناعة
اخر الاخبار
اخبار العتبة العباسية المقدسة
