Trial Watch

Abstract

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.

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

“…On 2015, Jan 6 th querying PubMed with the string "cancer AND (patients OR trial) AND (doxorubicin OR epirubicin OR idarubicin OR mitoxantrone OR bortezomib OR bleomycin OR cyclophosphamide OR oxaliplatin)" returned 48,701 entries, some 2,000 of which were published since the submission of our latest Trial Watch dealing with ICD-inducing chemotherapeutics (January 2014). 83 This figure obviously covers a number of preclinical research papers, review articles and editorials that is difficult to quantify with precision. Moreover, in a significant fraction of the clinical articles included in this figure, doxorubicin, epirubicin, idarubicin, mitoxantrone, bortezomib, bleomycin, cyclophosphamide and oxaliplatin are employed as part of standard chemotherapeutic regimens, in on-label indications (source (http://www.ncbi.nlm.…”

“…134 Recently initiated clinical trials. Since the submission of our latest Trial Watch dealing with this topic (January 2014), 83 In the vast majority of these trials (250 studies), however, ICD inducers are employed as onlabel therapeutic interventions, most often as (part of) the gold standard chemotherapeutic regimen given to the control arm of the study. These studies will not be discussed further here.…”

Consensus guidelines for the detection of immunogenic cell death

“…22 It turned out that the unsuspected ability of doxorubicin (an anthracycline employed for the treatment of various carcinomas) to trigger ICD as a standalone intervention, hence converting dying cancer cells into a vaccine that is efficient in the absence of adjuvants, is shared by a relatively restricted set of lethal triggers. [28][29][30][31][32][33] These include, but perhaps are not limited to, mitoxantrone and epirubicin (2 other anthracyclines currently used in the clinic), [34][35][36][37] bleomycin (a glycopeptide antibiotic endowed with antineoplastic properties), 38 oxaliplatin (a platinum derivative generally employed against colorectal carcinoma), [39][40][41][42] cyclophosphamide (an alkylating agent approved for the treatment of neoplastic and autoimmune conditions), [43][44][45][46][47][48] etoposide (a topoisomerase inhibitor currently used for the treatment of several neoplasms) combined with the chemical inhibitor of glycolysis 2-deoxyglucose, 49,50 patupilone (a microtubular inhibitor that has not yet been approved for use in humans), [51][52][53] septacidin (an antifungal antibiotic produced by Streptomyces fibriatus) 54,55 specific forms of radiation therapy, 34,[56][57][58][59][60][61][62][63][64] photodynamic therapy (a clinically approved antican...…”

STAT3 inhibition for cancer therapy: Cell-autonomous effects only?

“…13 Indeed, STAT3 inhibitors can be advantageously combined with immunogenic cell death (ICD)-inducing chemotherapeutic agents. 13 Given the clinical impact of ICD inducers, [15][16][17][18][19][20][21][22] it will be important to explore this possibility in properly designed trials.…”