The tyrosine kinase inhibitor (TKI) drug class is a prominently used option in the treatment of various cancers. Safety evaluation of these drugs has shown evidence of cardiotoxicity of varying frequency and severity between agents; concern has led to updated labeling, warning prescribers of such. This review seeks to clarify the present dangers and investigate cardiotoxic mechanisms of action for each discussed TKI. Dasatinib was connected primarily with an incidence of fluid retention, edema, QT prolongation, and pulmonary hypertension in clinical studies. It is theorized that this is due to a combination of off-target kinase binding and on-target binding of Bcr-Abl, and less likely, mitochondrial induced apoptosis. Studies showed sorafenib to carry the risk of hypertension, QT prolongation, and myocardial infarction. Proposed mechanisms for these side effects include inhibition of proteins, vascular endothelium growth factor receptor, hERG potassium channels, and the RAF/MERK/ERK pro-survival pathway. Finally, lapatinib showed evidence of decreased left ventricular ejection fraction (LVEF) and QT prolongation in clinical studies. The literature attributes these as side effects of on-target ErbB2 binding leading to mitochondrial induced apoptosis. The concern warranted by these findings is in question. Pooled safety data suggest that the overall risk for cardiotoxicity is minimal in dasatinib and lapatinib. Sorafenib seems to carry a moderate concern. For the discussed agents, recommendations agree that routine monitoring via methods such as electroencephalogram, cardiac biomarkers, and blood pressure is warranted during the course of treatment, in addition to a comprehensive collection of past medical history and risk factors to identify those at heightened risk for cardiovascular events.

Immuno-oncology (I-O) is a young and growing field on the frontier of cancer therapy. Contrary to cancer therapies that directly target malignant cells, I-O therapies stimulate the body’s immune system to target and attack the tumor, which is otherwise invisible to, or inhibiting the immune response. To this end, several methods have been developed: First, passive therapies that enable T-cells to fight the tumor without direct manipulation, typically through binding and modifying the intracellular signaling of surface receptors. Checkpoint inhibitors, perhaps the most well known of I-O therapies; are an example of such. These are monoclonal antibodies that block binding of the tumor cell at receptors that inactivate the T-cell. A variety of small molecules can achieve the same effect by affecting metabolic or signaling pathways to boost the immune response or prevent its attenuation. Drugs originally formulated for unrelated disease states are now being used to treat cancer under the I-O approach. Second, active therapies which often involve direct manipulations that occur in vitro and once introduced to the patient will directly attack the tumor. Adoptive cell transfer is the oldest of these methods. It involves the removal of T-cells from the body, which are then expanded and genetically modified for specificity toward tumor-associated antigens (TAAs), and then reintroduced to the patient. A similar approach is taken with cancer vaccines, where TAAs are identified and reintroduced with adjuvants to stimulate an immune response, sometimes in the context of antigen-presenting cells or viral vectors. Oncolytic viruses are genetically modified natural viruses for selectivity toward tumor cells. The resulting cytotoxicity has the potential to elicit an immune response that furthers tumor cell killing. A final active approach is bi-specific T-cell engagers. These modified antibodies act to link a T-cell and tumor cell through surface receptors and thereby forcibly generate immune recognition. The therapies in each of these subfields are all still very new and ongoing clinical trials could provide even further additions. The full therapeutic potential of the aforementioned therapies, alone or in combination, has yet to be realized, but holds great promise for the future of cancer treatment.

Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, DASATINIB; indicated for IMATINIB-refractory chronic myeloid leukemia, and SORAFENIB; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure. A greater understanding of the underlying mechanisms of this cardiotoxicity are needed as concerns grow and the capacity to anticipate them is lacking. The objective of this study was to explore the mitochondrial-mediated cardiotoxic mechanisms of the two selected TKIs. This was achieved experimentally using immortalized human cardiomyocytes, AC16 cells, to investigate dose- and time-dependent cell killing, along with measurements of temporal changes in key signaling proteins involved in the intrinsic apoptotic and autophagy pathways upon exposure to these agents. Quantitative systems pharmacology (QSP) models were developed to capture the toxicological response in AC16 cells using protein dynamic data. The developed QSP models captured well all the various trends in protein signaling and cellular responses with good precision on the parameter estimates, and were successfully qualified using external data sets. An interplay between the apoptotic and autophagic pathways was identified to play a major role in determining toxicity associated with the investigated TKIs. The established modeling platform showed utility in elucidating the mechanisms of cardiotoxicity of SORAFENIB and DASATINIB. It may be useful for other small molecule targeted therapies demonstrating cardiac toxicities, and may aid in informing alternate dosing strategies to alleviate cardiotoxicity associated with these therapies.

Introduction Immune checkpoint inhibitors (ICI) are novel oncolytic therapies associated with various immune related adverse events (irAEs) affecting multiple organ systems, which may have a delayed presentation. Identification of irAEs and prompt initiation of appropriate treatment represents a challenge to clinicians. The purpose of this study was to evaluate the effectiveness of a pharmacy consult service in identification and management of irAEs. Methodology: This was a single center, retrospective study. Patients included were: ≥18 years old, admitted as inpatients, and reported a history of cancer treatment within the last year. A pharmacy consult was developed and implemented for patients who reported a history of ICI therapy within the last year. Education regarding the consult service was provided to select physicians, nurses, and all pharmacists. Primary outcome: percent of admitted patients reporting ICI therapy within the last year, who required pharmacist intervention for an irAE. Secondary outcomes: types of interventions performed, percentage of recommendation acceptance, pharmacist time spent. Results Fifty-one patients received a pharmacy immunotherapy consult. Seventeen patients (33%) met the primary outcome. Thirty-three separate recommendations were made by pharmacists for these 17 patients. The secondary outcomes of interventions made and percentage accepted (n; % accepted): Initiation/adjustment of steroid therapy (20; 40%), placement of a consult for oncology or other specialist (10; 70%), other therapeutic interventions (3; 67%). Average time spent by pharmacist on initial consultations (SD): 29 minutes (15). Conclusion A pharmacy consult service may help to increase identification of patients receiving immune checkpoint inhibitors and initiate timely interventions.