This article explores recent advances in the design and engineering of materials wholly or principally constructed from peptides. We focus on materials that are able to respond to changes in their environment (pH, ionic strength, temperature, light, oxidation/reduction state, presence of small molecules or the catalytic activity of enzymes) by altering their macromolecular structure. Such peptide-based responsive biomaterials have exciting prospects for a variety of biomedical and bionanotechnology applications in drug delivery, bio-sensing and regenerative medicine.

Peptide-based stimuli-responsive biomaterials

Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering ‘unmaskable’ agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies. Limited penetration into tumour tissue can restrict the activity of systemically delivered cancer immunotherapies, whereas exposure of various non-malignant tissues to high levels of such agents can lead to problematic toxicities. Intratumoural administration and/or biotechnology strategies for selective targeting of tumour tissues have the potential to circumvent these issues and thereby increase the therapeutic index. Herein, the authors review the historical origins and current landscape of intratumoural and tumour tissue-targeted immunotherapies.

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Intratumoural administration and tumour tissue targeting of cancer immunotherapies

In vitro-transcribed messenger RNA-based therapeutics represent a relatively novel and highly efficient class of drugs. Several recently published studies emphasize the potential efficacy of mRNA vaccines in treating different types of malignant and infectious diseases where conventional vaccine strategies and platforms fail to elicit protective immune responses. mRNA vaccines have lately raised high interest as potent vaccines against SARS-CoV2. Direct application of mRNA or its electroporation into dendritic cells was shown to induce polyclonal CD4+ and CD8+ mediated antigen-specific T cell responses as well as the production of protective antibodies with the ability to eliminate transformed or infected cells. More importantly, the vaccine composition may include two or more mRNAs coding for different proteins or long peptides. This enables the induction of polyclonal immune responses against a broad variety of epitopes within the encoded antigens that are presented on various MHC complexes, thus avoiding the restriction to a certain HLA molecule or possible immune escape due to antigen-loss. The development and design of mRNA therapies was recently boosted by several critical innovations including the development of technologies for the production and delivery of high quality and stable mRNA. Several technical obstacles such as stability, delivery and immunogenicity were addressed in the past and gradually solved in the recent years.This review will summarize the most recent technological developments and application of mRNA vaccines in clinical trials and discusses the results, challenges and future directions with a special focus on the induced innate and adaptive immune responses.

/pdf/clinical-and-immunological-effects-of-mrna-vaccines-in-481ew66mbi.pdf

Clinical and immunological effects of mRNA vaccines in malignant diseases.

Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.

Nanobiomaterial-based vaccination immunotherapy of cancer.

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated “hot” tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts “cold” tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

https://www.pnas.org/content/pnas/early/2019/12/26/1904022116.full.pdf

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

Self-assembling peptides spontaneously associate into functional supramolecular scaffolds, which have found numerous biomedical applications. These molecular assemblies have applications in nerve regeneration, wound healing, and both prophylactic and therapeutic vaccination. They can also be useful tools for proliferation assays, sustained culture of difficult cell lines, or activation of cell lines for immunoassays. This protocol will describe the basic peptide synthesis and purification of model self-assembling peptide immunogen and methods for vaccinating mice, collecting lymph nodes, and stimulating cells ex vivo.

C. Brent Chesson

Papers

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

Microwave-Assisted Synthesis and Immunological Evaluation of Self-Assembling Peptide Vaccines