In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3)-blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naïve T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C. In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C potentiates immunotherapy by attracting naïve T cells, which are locally activated upon immunotherapy-induced tumor cell killing, and that serum VEGF-C may serve as a predictive biomarker for immunotherapy response.
Nanoparticle delivery systems are known to enhance the immune response to soluble antigens (Ags) and are thus a promising tool for the development of new vaccines. Our laboratory has engineered two different nanoparticulate systems in which Ag is either encapsulated within the core of polymersomes (PSs) or decorated onto the surface of nanoparticles (NPs). Previous studies showed that PSs are better at enhancing CD4 T cells and antibody titers, while NPs preferentially augment cytotoxic CD8 T cells. Herein, we demonstrate that the differential activation of T cell immunity reflects differences in the modes of intracellular trafficking and distinct biodistribution of the Ag in lymphoid organs, which are both driven by the properties of each nanocarrier. Furthermore, we found that Ags within PSs promoted better CD4 T cell activation and induced a higher frequency of CD4 T follicular helper (Tfh) cells. These differences correlated with changes in the frequency of germinal center B cells and plasma cell formation, which reflects the previously observed antibody titers. Our results show that PSs are a promising vector for the delivery of Ags for B cell vaccine development. This study demonstrates that nanocarrier design has a large impact on the quality of the induced adaptive immune response.
In melanoma, the induction of lymphatic growth (lymphangiogenesis) has long been correlated with metastasis and poor prognosis, but we recently showed it can synergistically enhance cancer immunotherapy and boost T cell immunity. Here, we develop a translational approach for exploiting this “lymphangiogenic potentiation” of immunotherapy in a cancer vaccine using lethally irradiated tumor cells overexpressing vascular endothelial growth factor C (VEGF-C) and topical adjuvants. Our “VEGFC vax” induced extensive local lymphangiogenesis and promoted stronger T cell activation in both the intradermal vaccine site and draining lymph nodes, resulting in higher frequencies of antigen-specific T cells present systemically than control vaccines. In mouse melanoma models, VEGFC vax elicited potent tumor-specific T cell immunity and provided effective tumor control and long-term immunological memory. Together, these data introduce the potential of lymphangiogenesis induction as a novel immunotherapeutic strategy to consider in cancer vaccine design.
Treatment of patients bearing human papillomavirus (HPV)-related cancers with synthetic long peptide (SLP) therapeutic vaccines has shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained elusive. We show that conjugation of a well-documented HPV-E7 SLP to ultra-small polymeric nanoparticles (NPs) enhances the antitumor efficacy of therapeutic vaccination in different mouse models of HPV + cancers. Immunization of TC-1 tumor-bearing mice with a single dose of NPconjugated E7LP (NP-E7LP) generated a larger pool of E7-specific CD8 + T cells with increased effector functions than unconjugated free E7LP. At the tumor site, NP-E7LP prompted a robust infiltration of CD8 + T cells that was not accompanied by concomitant accumulation of regulatory T cells (Tregs), resulting in a higher CD8 + T cell to Treg ratio. Consequently, the amplified immune response elicited by the NP-E7LP formulation led to increased regression of large, well-established tumors, resulting in a significant percentage of complete responses that were not achievable by immunizing with the non-NP-conjugated long-peptide. The partial responses were characterized by distinct phases of regression, stable disease, and relapse to progressive growth, establishing a platform to investigate adaptive resistance mechanisms. The efficacy of NP-E7LP could be further improved by therapeutic activation of the costimulatory receptor 4-1BB. This NP-E7LP formulation illustrates a 'solid-phase' antigen delivery strategy that is more effective than a conventional freepeptide ('liquid') vaccine, further highlighting the potential of using such formulations for therapeutic vaccination against solid tumors.
Therapeutic cancer vaccines constitute a valuable tool to educate the immune system to fight tumors and prevent cancer relapse. Nevertheless, the number of cancer vaccines in the clinic remains very limited to date, highlighting the need for further technology development. Recently, cancer vaccines have been improved by the use of materials, which can strongly enhance their intrinsic properties and biodistribution profile. Moreover, vaccine efficacy and safety can be substantially modulated through selection of the site at which they are delivered, which fosters the engineering of materials capable of targeting cancer vaccines to specific relevant sites, such as within the tumor or within lymphoid organs, to further optimize their immunotherapeutic effects. In this review, we aim to give the reader an overview of principles and current strategies to engineer therapeutic cancer vaccines, with a particular focus on the use of sitespecific targeting materials. We will first recall the goal of therapeutic cancer vaccination and the type of immune responses sought upon vaccination, before detailing key components of cancer vaccines. We will then present how materials can be engineered to enhance the vaccine's pharmacokinetic and pharmacodynamic properties. Finally, we will discuss the rationale for site-specific targeting of cancer vaccines and provide examples of current targeting technologies.
We have prepared triblock copolymers of poly(phenylene oxide) (PPO) and polysulphone (PSF) of the form PPO–PSF–PPO in order to assess their intrinsic mechanical properties and their potential as interfacial compatibilizers in polystyrene/PSF blends. For sufficiently long polysulphone block lengths, we observed microphase separation both in the triblock copolymers and in their blends with polystyrene. The triblock polymers, nevertheless, showed very similar microdeformation behavior to the PPO homopolymer, suggesting the phase separation to play a minor role. On the other hand, the compatibility of the poly(phenylene oxide) blocks and polystyrene ensured a high degree of interphase adhesion in blends containing both polystyrene and free PSF, even for relatively high homopolymer molecular weights. © 1996 John Wiley & Sons, Inc.
Vaccines are considered one of greatest successes of modern medicine; indeed, prophylactic vaccinations allow tight control of disease spreading and even eradication of some diseases. Vaccines immunize patients against known antigens derived from infectious agents, so that the immune system can efficiently block pathogen entry and mount a faster and better immune reaction in case of infection. In the context of cancer, finding good antigens for immunization against tumor cells can be challenging since tumor cells are derived from the self, and thus are not always efficiently recognized as malignant by the immune system. Here, we seek to develop a cancer immunotherapy that delivers a pre-encountered antigen to tumor cells to redirect the host pre-existing immunity against cancer. As a vaccine model, we used ovalbumin (OVA) antigen adjuvanted with CpG-B oligodeoxynucleotides to pre-immunize C57BL/6 mice, developing both T cell and B cell immunity against OVA. At least one month later, mice were challenged with B16-OVA melanoma cells. We observed that tumor growth in pre-immunized mice was slightly delayed compared to growth in naïve mice, but this effect was modest, leading to an overall 1-day increased survival. We reasoned that this effect could be improved by modifying the cellular localization of OVA antigen; indeed, OVA is expressed intracellularly in B16-OVA cells, thus excluding potential antibody-mediated anti-tumoral immune response. Therefore, we created a B16 melanoma cell line that overexpresses a membrane-bound OVA (B16memOVA), using similar design as published elsewhere (DiLillo et al., J. Immunol. 2010). In vitro, B16memOVA cells behaved similarly to the parental B16 cell line, and the growth of B16memOVA tumors in OVA-expressing mice (which are tolerant to OVA) was similar to the growth of B16 tumors, thus validating our B16memOVA tumor model. When implanted in naïve mice, B16memOVA tumors were able to grow, despite the onset of a neo-immune reaction against OVA, which slows tumor growth. In contrast, mice pre-immunized against OVA totally rejected B16memOVA tumors. Our efforts are now focusing on the development of an antigen-delivery method to trigger the expression of membrane-bound OVA in B16 tumors after implantation, to apply this approach in a therapeutic setup. Citation Format: Priscilla S. Briquez, Sylvie Hauert, Grégoire Repond, Melody A. Swartz, Jeffrey A. Hubbell. Exploiting host pre-existing immunity for melanoma cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1217.
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