Delivering safer immunotherapies for cancer

Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double-edged sword: Drugs that activate immune effectors are prone to serious non-specific systemic inflammation and autoimmune side effects. Drug delivery technologies have an important role to play in harnessing the power of immune therapeutics while avoiding on-target/off-tumor toxicities. Here we review mechanisms of toxicity for clinically-relevant immunotherapeutics, and discuss approaches based in drug delivery technology to enhance the safety and potency of these treatments. These include strategies to merge drug delivery with adoptive cellular therapies, targeting immunotherapies to tumors or select immune cells, and localizing therapeutics intratumorally. Rational design employing lessons learned from the drug delivery and nanomedicine fields has the potential to facilitate immunotherapy reaching its full potential

Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment

Systemic cancer immunotherapies including checkpoint blockade antibodies targeting the PD-1/PD-L1 axis and CTLA-4 have improved survival outcomes in a subset of cancer patients by driving tumor-directed immune responses. However, many patients do not benefit from such immunotherapies due to immune resistance mechanisms or severe inflammatory adverse events resulting in treatment discontinuation. Direct intratumoral injection of immunomodulatory agents has been successfully implemented to maximize immune stimulation at the site of the tumor while minimizing drug concentrations in systemic circulation. By focusing the immune response within a tumor of interest, immune cell killing of cancer cells releases tumor debris to which the immune system can be educated – effectively generating a tumor-specific vaccine. Localized inflammation in the tumor microenvironment additionally serves to adjuvant the in situ vaccination response. Ultimately, immune cells primed after intratumoral immunomodulation can traffic to distant sites of metastasis leading to tumor regressions at injected and non-injected lesions. The intratumoral in situ vaccination approach is amenable to a variety of therapeutic modalities ranging from small molecules, to proteins, and cell-based therapies. In this thesis, we present two combination immunotherapy regimen that take advantage of intratumoral injection. First, we describe an “off-the-shelf” in situ vaccine featuring locally administered small molecule activators of the STimulator of INterferon Genes (STING) pathway combined with systemically administered interleukin-2 and anti-PD-1 towards the generation of anti-tumor immunity in spontaneously metastatic breast tumor models. In this setting we detail the integration of immunotherapy with surgical resection and define the immune cell types mediating metastasis clearance. Taking a more personalized vaccine approach, we secondly demonstrate that in vitro treatment of tumor cells with DNA-damaging chemotherapy can promote tumor antigen-specific T cell activation by dendritic cells. Intratumoral injection of these chemotherapy-damaged cells synergizes with immune checkpoint blockade to promote tumor regression. Together, these studies underscore the versatility of intratumoral immunomodulation and highlight the wholistic activation of both innate and adaptive immune cells, hopefully contributing to more patients benefiting from cancer immunotherapy.Ph.D

Immunogenic cell stress and injury versus immunogenic cell death: implications for improving cancer treatment with immune checkpoint blockade

Inducing immunogenic tumor cell death to stimulate the response to immune checkpoint blockade has not yet been effectively translated into clinical practice. We recently discovered that stressed/injured but still viable tumor cells are critical for T-cell priming and substantially improve responses to systemic anti-PD1/CTLA4. Therapeutic tumor cell injury, rather than complete killing, in the tumor microenvironment may enhance efficacy of immunotherapy in various cancers

Delivering safer immunotherapies for cancer

Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double-edged sword: Drugs that activate immune effectors are prone to serious non-specific systemic inflammation and autoimmune side effects. Drug delivery technologies have an important role to play in harnessing the power of immune therapeutics while avoiding on-target/off-tumor toxicities. Here we review mechanisms of toxicity for clinically-relevant immunotherapeutics, and discuss approaches based in drug delivery technology to enhance the safety and potency of these treatments. These include strategies to merge drug delivery with adoptive cellular therapies, targeting immunotherapies to tumors or select immune cells, and localizing therapeutics intratumorally. Rational design employing lessons learned from the drug delivery and nanomedicine fields has the potential to facilitate immunotherapy reaching its full potential.National Institutes of Health (U.S.) (Grant CA206218)National Institutes of Health (U.S.) (Grant CA172164)National Institutes of Health (U.S.) (Grant CA174795

ABC triblock bottlebrush copolymer-based injectable hydrogels: design, synthesis, and application to expanding the therapeutic index of cancer immunochemotherapy

Bottlebrush copolymers are a versatile class of macromolecular architectures with broad applications in the fields of drug delivery, self-assembly, and polymer networks. Here, the modular nature of graft-through ring-opening metathesis polymerization (ROMP) is exploited to synthesize "ABC"triblock bottlebrush copolymers (TBCs) from polylactic acid (PLA), polyethylene glycol (PEG), and poly(N-isopropylacrylamide) (PNIPAM) macromonomers. Due to the hydrophobicity of their PLA domains, these TBCs self-assemble in aqueous media at room temperature to yield uniform ∼100 nm micelles that can encapsulate a wide range of therapeutic agents. Heating these micellar solutions above the lower critical solution temperature (LCST) of PNIPAM (∼32 °C) induces the rapid formation of multi-compartment hydrogels with PLA and PNIPAM domains acting as physical crosslinks. Following the synthesis and characterization of these materials in vitro, TBC micelles loaded with various biologically active small molecules were investigated as injectable hydrogels for sustained drug release in vivo. Specifically, intratumoral administration of TBCs containing paclitaxel and resiquimod-the latter a potent Toll-like receptor (TLR) 7/8 agonist-into mice bearing subcutaneous CT26 tumors resulted in a significantly enhanced therapeutic index compared to the administration of these two drugs alone. This effect is attributed to the TBC hydrogel maintaining a high local drug concentration, thus reducing systemic immune activation and local inflammation. Collectively, this work represents, to our knowledge, the first example of thermally-responsive TBCs designed for multi-compartment hydrogel formation, establishing these materials as versatile scaffolds for self-assembly and drug delivery.National Institutes of Health (Grant 1R01CA220468-01)National Institute of General Medical Sciences (Grant T32-GM008334

The injury response to DNA damage in live tumor cells promotes antitumor immunity

Inducing a DNA damage response in tumor cells ex vivo creates an immunogenic live-cell adjuvant.</jats:p