Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named “immunogenic cell death” (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

The term “immunogenic cell death” (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into bona fide ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based on ICD inducers.

In 1997, for the first time in history, a monoclonal antibody (mAb), i.e., the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug Administration for use in cancer patients. Since then, the panel of mAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has not stopped to expand, nowadays encompassing a stunning amount of 15 distinct molecules. This therapeutic armamentarium includes mAbs that target tumor-associated antigens, as well as molecules that interfere with tumor-stroma interactions or exert direct immunostimulatory effects. These three classes of mAbs exert antineoplastic activity via distinct mechanisms, which may or may not involve immune effectors other than the mAbs themselves. In previous issues of OncoImmunology, we provided a brief scientific background to the use of mAbs, all types confounded, in cancer therapy, and discussed the results of recent clinical trials investigating the safety and efficacy ...

Accumulating evidence suggests that the clinical efficacy of selected anticancer drugs, including conventional chemotherapeutics as well as targeted anticancer agents, originates (at least in part) from their ability to elicit a novel or reinstate a pre-existing tumor-specific immune response. One of the mechanisms whereby chemotherapy can stimulate the immune system to recognize and destroy malignant cells is commonly known as immunogenic cell death (ICD). Cancer cells succumbing to ICD are de facto converted into an anticancer vaccine and as such elicit an adaptive immune response. Several common chemotherapeutics share the ability of triggering ICD, as demonstrated in vaccination experiments relying on immunocompetent mice and syngeneic cancer cells. A large number of ongoing clinical trials involve such ICD inducers, often (but not always) as they are part of the gold standard therapeutic approach against specific neoplasms. In this Trial Watch, we summarize the latest advances on the use of cyclophosphamide, doxorubicin, epirubicin, oxaliplatin, and mitoxantrone in cancer patients, discussing high-impact studies that have been published during the last 13 months as well as clinical trials that have been initiated in the same period to assess the antineoplastic profile of these immunogenic drugs as off-label therapeutic interventions.