After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.

T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas-FasL in antigen-specific T-cell killing. We also found that Fas-FasL mediated off-target "bystander" killing of antigen-negative tumor cells. This localized bystander cytotoxicity enhanced clearance of antigen-heterogeneous tumors in vivo, a finding that has not been shown previously. Fas-mediated on-target and bystander killing was reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T-cell models and was augmented by inhibiting regulators of Fas signaling. Tumoral FAS expression alone predicted survival of CAR-T-treated patients in a large clinical trial (NCT02348216). These data suggest strategies to prevent immune escape by targeting both the antigen expression of most tumor cells and the geography of antigen-loss variants.SigNifiCANCe: This study demonstrates the first report of in vivo Fas-dependent bystander killing of antigen-negative tumors by T cells, a phenomenon that may be contributing to the high response rates of antigen-directed immunotherapies despite tumoral heterogeneity. Small molecules that target the Fas pathway may potentiate this mechanism to prevent cancer relapse. intRoductionT cell-based immunotherapies-including adoptive transfer of engineered T cells, bispecific antibodies, and checkpoint blockade-have revolutionized cancer treatment. However, even with the remarkably high response rates of chimeric antigen receptor (CAR)-T-treated patients, most either progress or relapse within one year (1-3). Microenvironmental factors contributing to T-cell priming (4-6) and T cell-intrinsic factors (7, 8) both influence antitumor immunity, but tumor cell-intrinsic factors have the most abundant clinical evidence for contributing to treatment potency and failures.The clearest such mechanism is target antigen (Ag) modulation-expression downregulation, lineage switching, or emergence of splice variants-which is the most common cause of relapse following CAR-T therapy for B-cell acute

There is an urgent need to develop new life‐prolonging therapy for pancreatic ductal adenocarcinoma (PDAC). It is demonstrated that improved irinotecan delivery by a lipid bilayer coated mesoporous silica nanoparticle, also known as a silicasome, can improve PDAC survival through a chemo‐immunotherapy response in an orthotopic Kras‐dependent pancreatic cancer model. This discovery is premised on the weak‐basic properties of irinotecan, which neutralizes the acidic lysosomal pH in PDAC cells. This effect triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death (ICD), and programmed death‐ligand 1 (PD‐L1) expression. ICD is characterized by calreticulin expression and high‐mobility group box 1 (HMGB1) release in dying Kras‐induced pancreatic cancer (KPC) cells, which is demonstrated in a vaccination experiment to prevent KPC tumor growth on the contralateral site. The improved delivery of irinotecan by the silicasome is accompanied by robust antitumor immunity, which can be synergistically enhanced by anti‐PD‐1 in the orthotopic model. Immunophenotyping confirms the expression of calreticulin, HMGB1, PD‐L1, and an autophagy marker, in addition to perforin and granzyme B deposition. The chemo‐immunotherapy response elicited by the silicasome is more robust than free or a liposomal drug, Onivyde. The silicasome plus anti‐PD‐1 leads to significantly enhanced survival improvement, and is far superior to anti‐PD‐1 plus either free irinotecan or Onivyde.

In this study a mesoporous silica nanoparticle (MSNP) based platform is developed for high‐dose loading of a range of activated platinum (Pt) chemo agents that can be attached to the porous interior through the use of electrostatic and coordination chemistry under weak‐basic pH conditions. In addition to the design feature for improving drug delivery, the MSNP can also be encapsulated in a coated lipid bilayer (silicasome), to improve the colloidal stability after intravenous (IV) injection. Improved pharmacokinetics and intratumor delivery of encapsulated activated oxaliplatin (1,2‐diamminocyclohexane platinum(II) (DACHPt)) over free drug in an orthotopic Kras‐derived pancreatic cancer (PDAC) model is demonstrated. Not only does IV injection of the DACHPt silicasome provide more efficacious cytotoxic tumor cell killing, but can also demonstrate that chemotherapy‐induced cell death is accompanied by the features of immunogenic cell death (ICD) as well as a dramatic reduction in bone marrow toxicity. The added ICD features are reflected by calreticulin and high‐mobility group box 1 expression, along with increased CD8+/FoxP3+ T‐cell ratios and evidence of perforin and granzyme B release at the tumor site. Subsequent performance of a survival experiment, demonstrates that the DACHPt silicasome generates a significant improvement in survival outcome, which can be extended by delayed administration of the anti‐PD‐1 antibody.

Macrophages are abundant immune cells, which serve as a primary cell population capable of interacting with foreign substances, including engineered nanomaterials (NMs). In addition to the phagocytic activity, macrophages also play a central role in innate immunity and contribute to the initiation of adaptive immunity. Since macrophages are a natural reservoir for NMs, nanoparticles (or nano-enabled strategies) are commonly utilized to target this cell type and fine tune its polarization status in different disease scenarios. In this review, a high-level description of macrophage biology is first introduced. It is followed by the discussion on the impact of therapeutic NMs on macrophages in solid tumors and how macrophages, in turn, impact the immune system and heterogeneity in the tumor microenvironment. Another major thrust is to discuss the applications of NMs in noncancer diseases with a focus on how NMs can be used to influence macrophages in the process of tissue repair, wound healing, myocardial infarction, and certain autoimmune diseases. In addition to the design of nanocarriers to impact macrophage function, whether the same response outcome can be achieved by intrinsic NM's physicochemical properties, allowing the potential usage of the active pharmaceutical ingredient-free nanomaterials for therapeutic purposes, is also discussed.