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Landmark successes in oncoimmunology have led to development of therapeutics boosting the host immune system to eradicate local and distant tumors with impactful tumor reduction in a subset of patients. However, current immunotherapy modalities often demonstrate limited success when involving immunologically cold tumors and solid tumors. Here, we describe the role of various biomaterials to formulate cancer vaccines as a form of cancer immunotherapy, seeking to utilize the host immune system to activate and expand tumor-specific T cells. Biomaterial-based cancer vaccines enhance the cancer-immunity cycle by harnessing cellular recruitment and activation against tumor-specific antigens. In this review, we discuss biomaterial-based vaccine strategies to induce lymphocytic responses necessary to mediate anti-tumor immunity. We focus on strategies that selectively attract dendritic cells via immunostimulatory gradients, activate them against presented tumor-specific antigens, and induce effective cross-presentation to T cells in secondary lymphoid organs, thereby generating immunity. We posit that personalized cancer vaccines are promising targets to generate long-term systemic immunity against patient- and tumor-specific antigens to ensure long-term cancer remission.

Background Pancreatic adenocarcinoma (PDAC) is associated with extremely poor prognosis and a 5-year survival rate of 10% and remains a lethal malignancy. Surgical resection and combination with chemoradiotherapy are the current standard-of-care options, may improve long-term survival in localized disease; however, the majority of patients are diagnosed at advanced stage. The incorporation of immunotherapy in the treatment algorithm convenes a new era for PDAC treatment. Several immunotherapy approaches have been investigating for treating PDAC such as checkpoint inhibitors, vaccines, adoptive cell therapy, and so on. Immunotherapy has been shown as a promising therapeutic method for many cancer types; however, the complexity and immunosuppressive of the solid tumor microenvironment (TME) results in limited treatment efficacy for PDAC. Methods To sensitize the TME in response to immunotherapy, we developed an implantable intratumoral drug delivery device, Nanofluidic Drug-Eluting Seed (NDES) can be injected via a minimally invasive trocar system that feasible for the clinical setting. NDES has shown efficiently delivered immunotherapy to murine breast cancer model and reduced tumor burden and showed low liver inflammation compared to the intraperitoneal delivery approach in the previous study.1 2 Here, we utilized NDES for the sustained intratumoral delivery of the CD40 antibody. We compared the efficacy of NDES against intraperitoneal and intratumoral administration, which mimics conventional systemic treatment. Tumor growth was investigated for treatment efficacy. Local and systemic immune responses were assessed via flow cytometry. Results NDES delivered CD40 significantly reduced tumor burden, some even achieved tumor clearance. Local NDES CD40 delivery approach showed a systemic increase of CD8+ and CD4+ T cells in the tumor-draining lymph node and spleen by flow cytometry. Furthermore, NDES CD40 treated mice showed an increase of CD8+ and CD4+ central memory T cells locally and systemically. We also investigated the combination with radiotherapy, no significant difference in tumor burden was observed when compared to single-agent CD40 antibody. The results indicated CD40 promotes TME response and improved treatment efficacy. Conclusions These immunological responses demonstrate ‘cold’ to ‘hot’ tumor transformation, which translated to tumor burden reduction. Overall, NDES delivery strategy offers promise for enhancing therapeutic index and transforming the landscape of PDAC tumor therapy. References Liu H-C, Viswanath D, Pesaresi F, et al. Potentiating antitumor efficacy through radiation and sustained intratumoral delivery of anti-CD40 and anti-PDL1. Int J Radiat Oncol Biol Phys 2020;S0360-3016(20)33745-7. Chua CYX, Jain P, et al. Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer. J Control Release 2018;285:23–34.

Background Personalized therapeutic cancer vaccines aim to target and reprogram the host immune system to achieve cancer eradication in situ. Cancer vaccines deliver two main components: immunostimulants (iS) and tumor antigens to reduce tumor burden with a robust T cell response; however, none have reached broad clinical success due to difficulty in vaccine administration, ex vivo cellular manipulation, low clinical efficacy and broad administrative barriers. While most efforts to date have focused on repeated bolus administrations, biomaterial-based vaccine strategies have led to promising clinical translation. Methods In light of these challenges, we have designed a clinically-viable platform-based vaccine strategy, termed the NanoLymph, to provide spatiotemporal elution of immunostimulants and tumor antigens locally to recruit and activate antitumor immunity for cancer eradication. Here, we aim to target the release of granulocyte macrophage colony stimulating factor (GM-CSF) and TLR-7/8 agonist Resiquimod (R848) to promote recruitment and activation of dendritic cells (DCs), a key player in antitumor cytotoxicity. Results We demonstrate the NanoLymph as an structurally stable and biocompatible immunostimulatory niche for durable DC-driven tumor specific T-cell mediated cytotoxicity. Additionally, we demonstrate the NanoLymph’s ability to recruit and activate immune cells of interest, activating antitumor immunity against model antigen. Thus, we have provided the framework necessary to develop a personalized therapeutic cancer vaccine for tumor-specific T-cell mediated responses necessary to generate immunological memory. Conclusions Future studies will evaluate immunostimulant and tumor antigen biodistribution in vivo and further apply the NanoLymph in a tumor bearing model to effect antitumor cytotoxicity. Ultimately, we aim to develop a personalized platform applicable for every patient of any cancer type aimed at direct clinical translation. Ethics Approval This study was approved by the Houston Methodist Research Institute (HMRI), according to protocols approved by the Institutional Animal Care and Use Committee (IACUC). HMRI’s Animal Welfare Assurance number is A4555-01. HMRI assures strict compliance with all federal regulations and guidelines involving the use of laboratory animals in biomedical research.

Purpose Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. Methods and Materials We used a nanofluidic drug-eluting seed (NDES) for sustained intratumoral delivery of combinational antibodies CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer. We compared the efficacy of NDES against intraperitoneal administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. Results The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden. Conclusions Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.

Probiotics exert multiple health benefits, including gastrointestinal health, immunoregulation, and metabolic disease improvement, by modulating microbiota to maintain eubiosis via the hypothalamic&ndash, pituitary&ndash, adrenal (HPA) and brain&ndash, gut&ndash, microbiome axes. Physiological fatigue, mental stress, and gastrointestinal discomfort under the demands of athletic performance as well as immunosuppression are common during endurance training and competition. Limited studies investigated the functional effects of probiotic supplementation on endurance training. Bifidobacterium longum subsp. Longum OLP-01 (OLP-01), isolated from an elite Olympic athlete, was combined with a six-week exercise training program with gradually increasing intensity. In this study, Institute of Cancer Research (ICR) mice were assigned to sedentary, exercise, OLP-01, or exercise + OLP-01 groups and administered probiotic and/or treadmill exercise training for six weeks to assess exercise performance, physiological adaption, and related metabolites. The exercise + OLP-01 group demonstrated higher performance in terms of endurance and grip strength, as well as improved fatigue-associated indexes (lactate, ammonia, creatine kinase (CK), lactate dehydrogenase (LDH), and glycogen content), compared with the other groups. OLP-01 supplementation significantly ameliorated inflammation and injury indexes (platelet/lymphocyte ratio (PLR), aminotransferase (AST), and CK) caused by prolonged endurance exercise test. Moreover, acetate, propionate, and butyrate levels were significantly higher in the exercise + OLP-01 group than in the sedentary and OLP-01 groups. Athletes often experience psychological and physiological stress caused by programed intensive exercise, competition, and off-site training, often leading to poor exercise performance and gastrointestinal issues. Functional OLP-01 probiotics are considered to be a nutritional strategy for improving physiological adaption, oxidative stress, inflammation, and energy balance to ensure high physical performance. Based on these results, probiotics combined with exercise training is a potential strategy for ensuring high physical performance of athletes, which should be further investigated through microbiota validation.

Cell encapsulation is an attractive transplantation strategy to treat endocrine disorders. Transplanted cells offer a dynamic and stimulus-responsive system that secretes therapeutics based on patient need. Despite significant advancements, a challenge in allogeneic cell encapsulation is maintaining sufficient oxygen and nutrient exchange, while providing protection from the host immune system. To this end, we developed a subcutaneously implantable dual-reservoir encapsulation system integrating in situ prevascularization and local immunosuppressant delivery, termed NICHE. NICHE structure is 3D-printed in biocompatible polyamide 2200 and comprises of independent cell and drug reservoirs separated by a nanoporous membrane for sustained local release of immunosuppressant. Here we present the development and characterization of NICHE, as well as efficacy validation for allogeneic cell transplantation in an immunocompetent rat model. We established biocompatibility and mechanical stability of NICHE. Further, NICHE vascularization was achieved with the aid of mesenchymal stem cells. Our study demonstrated sustained local elution of immunosuppressant (CTLA4Ig) into the cell reservoir protected transcutaneously-transplanted allogeneic Leydig cells from host immune destruction during a 31-day study, and reduced systemic drug exposure by 12-fold. In summary, NICHE is the first encapsulation platform achieving both in situ vascularization and immunosuppressant delivery, presenting a viable strategy for allogeneic cell transplantation.

Background Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors. Methods Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence. Results We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8+ T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8+ effector T cells. Conclusions Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors. Electronic supplementary material The online version of this article (10.1186/s40425-019-0698-6) contains supplementary material, which is available to authorized users.

HPV-driven head and neck squamous cell carcinoma (HNSCC) are among the fastest growing cancers. Although, HPV-HNSCC patients have an overall favorable prognosis, a significant number of patients relapse post-treatment, and currently there is no specific therapeutic approach targeting the unique biology of HPV-driven HNSCC. Our ongoing efforts to target HPV-HNSCC focus on the identification of cell surface antigens that are upregulated by HPV infection. We have developed an "antigen-agnostic" approach for generating HPV-HNSCC-targeting monoclonal antibodies for cancer diagnosis and treatment that does not rely on prior identification of target antigens. We used HPV-HNSCC membrane fractions to immunize recipient mice and generated HPV-specific hybridomas. We then screened five thousand hybridoma colonies by flow cytometry to test the specificity of binding to HPV-positive cancer cell lines (2HNSCC and 2 Cervical Cancer) and HPV-negative cancer cell lines (4 HNSCC and 1 CC). After primary screening, we narrowed down to forty-four clones; among these hybridoma clones, 6D8 and 6B3 bound preferentially to HPV-positive cancer cell lines. The binding targets of 6D8 and 6B3 were identified by immunoprecipitation and mass spectrometry; their targets are integrin alpha6 (ITGA6) and tissue factor (F3) respectively. Future work will validate the biological function of these mAbs in in vitro and in vivo models, and continue identifying more binding target of mAbs. We propose mAbs specifically targeting membrane-expressed antigens on HPV-related cancer cells as a potential approach for early diagnosis and targeted therapy. Citation Format: Hsuan-Chen Liu, Falguni Parikh, Thomas Kraus, Thomas Moran, Andrew Sikora. Characterization of monoclonal antibodies specific for HPV-positive head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2211. doi:10.1158/1538-7445.AM2017-2211

A single-layer of breath figure pattern was explored via the dynamical optical images and the temperature evolution. The pattern was prepared with the solution of carbon disulfide (CS(2)) dissolved 1% weight concentration of polystyrene. The evaporation of CS(2) was considered to be the most important role to the formation of the breath figure pattern. The understanding of the breath figures pattern will promote the technique to fabricating an imprinted template with demanded hexagonal structures.