Immunotherapeutic role of cabazitaxel treatment in the activation of TLR3 signalling in metastatic castration-resistant prostate cancer in vitro.

BACKGROUND: The activation of toll like receptors (TLR) potentially affect the inflammatory tumor microenvironment and thus is associated with tumor growth or inhibition. Cabazitaxel (CAB) has been effectively used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the immune regulatory role of CAB in the tumor microenvironment is not clear. In this context, we for the first time assessed the immunotherapeutic role of CAB in the TLR3 signalling following activation of Poly I:C in mCRPC cells. METHODS AND RESULTS: The cytotoxic and apoptotic effects of CAB with the induction of Poly I:C were determined by WST-1, Annexin V, acridine orange, RT-PCR analysis, ELISA assay and immunofluorescence staining in DU-145 mCRPC and HUVEC control cells. Our findings showed that CAB treatment with Poly I:C significantly suppressed the proliferation of DU-145 cells through the induction of apoptosis and caspase activation. Additionally, higher concentration of CAB mediated the activation of TLR3 via increased cytoplasmic and nuclear expression of TLR3, TICAM-1 and IRF-3 in mCRPC cells. CONCLUSIONS: Co-treatment of CAB and Poly I:C was more effective in mCRPC cells with less toxicity in control cells. However, further investigations are required to elucidate the molecular mechanisms of TLRs signalling upon CAB treatment at the molecular level to further validate the immunotherapeutic efficacy of CAB in mCRPC.

Rapid desensitization to antineoplastic drugs in an outpatient immunoallergology clinic: Outcomes and risk factors.

BACKGROUND: Hypersensitivity reactions to antineoplastic agents may lead to discontinuation of first-line treatments. Rapid drug desensitization (RDD) allows for a safe reintroduction in patients who are allergic to them. OBJECTIVE: To evaluate the safety and efficacy of the Brigham and Women's Hospital's 12-step RDD in a Portuguese patient population with cancer and to identify markers associated with breakthrough reactions (BTRs) to platins. METHODS: We conducted a retrospective review of desensitizations undertaken at the Immunoallergology Day-Care Unit of the Santa Maria Hospital in Lisbon, Portugal, from July 2008 to July 2019. Adult patients with cancer and with immediate hypersensitivity reactions were included. Skin testing was performed to platins, trastuzumab, and cetuximab. The 12-step protocol was used for most patients, and a shorter protocol was used in 9 patients who were taxane-reactive to resume regular infusions. RESULTS: A total of 1471 RDDs were performed in 272 patients to 136 platins, 124 taxanes, 13 monoclonal antibodies, and 10 other drugs. Skin test results were positive in 127 of patients who were platin-reactive (95.3%) and negative in patients who were cetuximab- and trastuzumab-reactive. There were 141 BTRs during RDD (9.6% of infusions), 79.4% induced by platins with the majority having mild reactions (68.8%). There were 8 patients who were paclitaxel-reactive, and who completed a shorter protocol and resumed regular infusions successfully. Multiple platin infusions (cutoff: ≥10) and total immunoglobulin E greater than or equal to 100 U/mL were identified as independent risk factors for BTRs in patients who were platin-reactive. CONCLUSION: This large single-center study confirmed the safety and efficacy of the 12-step RDD protocol in a diverse cancer population, providing evidence of its universal applications. Total immunoglobulin E is a potentially useful biomarker to identify high-risk patients who are platin-reactive.

Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions.

BACKGROUND: The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. OBJECTIVE: We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. METHODS: Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. RESULTS: Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. CONCLUSIONS: Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions.

Evaluation and management of hypersensitivity reactions to chemotherapy agents.

Hypersensitivity reactions to chemotherapy drugs pose significant difficulties in management, especially when no suitable alternative is available or acceptable and delay in continuation of treatment may be life-threatening. Such reactions may be IgE- or non-IgE-mediated and have varied manifestations. Timely recognition and treatment of life-threatening hypersensitivity reactions are essential. Identification of patients at high risk of developing hypersensitivity reactions allows risk stratification to guide clinical decision-making. Skin testing for carboplatin hypersensitivity has good predictive value but is not yet established for oxaliplatin and taxane hypersensitivity. Rapid desensitisation may be considered if no suitable alternative drug is available. Available protocols have shown good safety and efficacy but must be performed in an appropriate setting with adequate monitoring. There are many avenues for research into the utility of skin testing for other chemotherapy agents as well as in vitro tests.

Diagnostic tools for hypersensitivity to platinum drugs and taxanes: skin testing, specific IgE, and mast cell/basophil mediators.

Hypersensitivity reactions (HSRs) to platinum drugs and taxanes are increasing in cancer patients, and rapid drug desensitization has emerged as a safe and effective method to reintroduce these drugs in reactive patients. Optimal management of patients presenting HSRs to chemotherapy depends on the use of various diagnostic tools, which include measurement of mast cell/basophil mediator release following a HSR and skin testing. Serum tryptase should be measured in patients presenting chemotherapy HSRs, and its elevation would support mast cell/basophil activation. Skin testing to platinum drugs has a high sensitivity and specificity and is critical to guide the management of platinum-reactive patients. Taxane skin testing is also emerging as a useful diagnostic and risk stratification tool in the evaluation of patients with HSRs to taxanes. Platinum sIgE assays have been recently developed and can be helpful in combination with skin testing or as an alternative when skin testing is not available.

Treatment outcomes of rapid desensitisation protocols for chemotherapeutic agents and monoclonal antibodies following hypersensitivity reactions.

BACKGROUND: Hypersensitivity reactions (HSR) to chemotherapeutic agents and monoclonal antibodies are common and may limit further therapeutic options. Drug desensitisation aims to induce a temporary clinical unresponsiveness to drug antigens so the causative drugs of HSR can continue to be administered. Rapid desensitisation using standardised protocols has been conducted by the Department of Immunology at The Canberra Hospital for patients who developed HSR to chemotherapeutic agents and monoclonal antibodies. AIMS: This retrospective audit reviewed the safety and efficacy of the desensitisation protocols used for patients across the Capital Region Cancer Service (CRCS). METHODS: Patients across the CRCS who received rapid desensitisation were identified through a search of archived correspondence. Clinical files and pharmacy records were analysed to determine protocol safety and efficacy. RESULTS: From June 2006 to July 2013, 13 patients underwent rapid desensitisations to oxaliplatin, carboplatin, docetaxel or rituximab. A total of 25 desensitisations was conducted with 21 (84%) achieving full target dose without inducing recurrent HSR. As a result, nine patients were successfully desensitised and continued to receive treatment without any further HSR. Desensitisation was aborted in three patients because of recurrence of HSR, which was not of a greater severity than the initial HSR. After successful desensitisation, seven patients were able to resume the regular protocols without requiring additional supervision. CONCLUSION: Rapid desensitisation to various chemotherapeutic agents and monoclonal antibodies with standardised protocols used across CRCS is safe and effective; it provides a feasible treatment option enabling continuation of effective regimens in the setting of HSR.

Desensitization regimens for drug allergy: state of the art in the 21st century.

Adverse reactions to drugs are increasingly being recognized as important contributions to disease in their own right as well as impediments to the best treatment of various conditions, including infectious, autoimmune, and neoplastic maladies. Rapid drug desensitization (RDD) is an effective mechanism for safely administering important medications while minimizing or entirely circumventing such adverse reactions in sensitized patients. We reviewed the literature on RDD in the last 10 years, including our experience from the Brigham and Women's Hospital Desensitization Program with hundreds of patients desensitized to a broad variety of drugs. RDD in our programme has been uniformly successful in patients with hypersensitivity reactions to antibiotics, chemotherapeutics, and monoclonal antibodies. Any reactions that occur during desensitization are generally much less severe than the initial hypersensitivity reaction to the drug, and patients have received the full dose of the desired medication 99.9% of the time out of (796) desensitizations. To date, there have been no fatalities. RDD is a safe and highly effective method for treating sensitized patients with the optimal pharmacologic agents. Its use should be expanded, but because patient safety is paramount, protocols must be created, reviewed, and overseen by allergist-immunologists with special training and experience in modern techniques of desensitization.

Hypersensitivity reactions to docetaxel: retrospective evaluation and development of a desensitization protocol.

BACKGROUND: Docetaxel (DT) is an extensively used taxane, frequently associated with hypersensitivity reactions. The aim of this study was to record the epidemiological and clinical features of hypersensitivity to DT in non-small cell lung cancer patients in order to obtain useful information concerning the management of these patients. We also developed a desensitization protocol and evaluated its clinical application. METHODS: We retrospectively reviewed records of 620 non-small cell lung cancer patients treated with DT-containing regimens in the adjuvant, first-, second- or next-line setting. Data from 102 patients who had exhibited hypersensitivity reactions were analyzed according to the Common Toxicity Criteria for Adverse Events version 3.0. Five patients were chosen for the desensitization protocol. We applied the standard protocol for parenteral desensitization to ß-lactam antibiotics, and DT treatment was carried out with a series of 10-fold dilutions in sufficient volume to administer the total dose. RESULTS: One hundred and two patients (16.5%) were recorded as having hypersensitivity to DT. Reactions were observed after approximately 2.5 ± 1.0 cycles. Only 14 patients (14/620, 2%) developed grade 3-4 hypersensitivity. Reactions were more likely in patients during second- or third-line chemotherapy, but no other correlation (age, gender, atopic status) was observed. Five patients completed a parenteral desensitization protocol and continued their treatment uneventfully. CONCLUSIONS: Hypersensitivity reactions to DT respond quickly to discontinuation along with appropriate supportive care. Premedication and increased infusion time may allow readministration. The desensitization protocol that we developed provides a reliable alternative to permanent discontinuation of DT.

Development of an enzyme-linked immunosorbent assay system to determine the presence of antibodies specific for taxane structures.

Taxanes, which are widely used in treatment of numerous cancer types, are well-known to induce hypersensitivity reactions (HSR), especially in the case of paclitaxel. Although the cause of the HSR is commonly thought to be a non-immunological direct effect of the diluent which is used to dissolve paclitaxel, some reports suggest the possibility of the presence of an immunological reaction to the common taxane structure. The aim of this study was to establish a method to determine the presence of anti-taxane antibodies in body fluids of patients who have previously received paclitaxel, in order to estimate the risk of the occurrence of HSR to other taxane compounds, such as docetaxel. To prepare an enzyme-linked immunosorbent assay (ELISA) plate for determining taxanes, 10-deacetylbaccatin III (DAB) was first succinylated by use of dimethylaminopyridine and succinic anhydride in dried pyridine. After the succinylation reaction, three different products were obtained, and these were confirmed as 7-succinoyl DAB (7-DAB), 10-succinoyl DAB (10-DAB), and 7,10-disuccinoyl DAB (7,10-DAB) by (1)H-NMR analysis. Each of these three products was conjugated with bovine serum albumin (BSA), and adsorbed on an ELISA plate. By using a commercially available anti-taxane monoclonal antibody as a model antibody, the detection limit of the anti-taxane antibodies on the 7-DAB-BSA-, 10-DAB-BSA-, and 7,10-DAB-BSA-conjugated ELISA plate was estimated as 0.3, 1 and 10 ng/ml, respectively. The ELISA system established in this study may therefore be useful for estimating the risk of HSR to taxanes in a patient prior to the use of these drugs.

Management of Hypersensitivity Reactions to Taxanes.

Taxanes are an important class of antineoplastic agents used in the treatment of a wide variety of cancers. However, paclitaxel and docetaxel, which are the most commonly used taxanes, elicit immediate hypersensitivity reactions (HSRs) in 5% to 10% of patients. Almost all patients that experience these reactions can be safely re-exposed to taxanes either through desensitization or challenge. This article describes the clinical presentation, diagnosis, and management of HSRs to taxanes and discusses the different options for their safe readministration.

Development of a piezoelectric immunosensor for the measurement of paclitaxel.

This paper describes the development of a piezoelectric immunosensor for the measurement of paclitaxel (taxol), a natural anti-cancer agent. An antibody specific for taxanes was immobilized onto the surface of quartz crystals by means of the layer-by-layer self-assembly technique. The immobilization was achieved using electrostatic interactions between a precursor layer and the antibody molecules. The assembly process was monitored by a quartz crystal microbalance (QCM) and the topography of the modified quartz crystals was investigated by means of atomic force microscopy. The specific interaction of the immobilized antibody with paclitaxel in solution at different concentrations was monitored as a change in resonant frequency of the modified crystal. Moreover, the influence of non-specific adsorption was also characterized. The results show that the proposed immunosensor offers a promising alternative to classical analytical methods for a fast and easy determination of paclitaxel.

Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer.

Paclitaxel, a class of taxane with microtubule stabilising ability, has remained with platinum based therapy, the standard care for primary ovarian cancer management. A deeper understanding of the immunological basis and other potential mechanisms of action together with new dosing schedules and/or routes of administration may potentiate its clinical benefit. Newer forms of taxanes, with better safety profiles and higher intratumoural cytotoxicity, have yet to demonstrate clinical superiority over the parent compound.

The immunopharmacology of paclitaxel (Taxol), docetaxel (Taxotere), and related agents.

Paclitaxel (Taxol) and docetaxel (Taxotere) are among the most unique, and successful, chemotherapeutic agents used for the treatment of breast and ovarian cancer. Both agents have anti-mitotic properties derived from binding to tubulin and excessive stabilization of microtubules. Their anti-neoplastic effects derive from this mechanism. Distinct from their effects on microtubule stabilization, paclitaxel, docetaxel, and related taxanes display immunopharmacological traits. In this review, we discuss their induction of pro-inflammatory genes and proteins; the current hypotheses on the molecular mechanism for this induction, especially its relationship to the lipopolysaccharide (LPS) signaling pathway. We also discuss the structure-activity relationships (SAR) that govern gene induction, especially the striking differences between the SAR for murine and human cells in vitro. Lastly, we discuss the immunopharmacological traits of paclitaxel and docetaxel in terms of their relevance to human clinical pharmacology and toxicology and their activity in animal models of autoimmune disorders.

Fatal hypersensitivity pneumonitis associated with docetaxel.

We present a patient with advanced breast cancer treated with three cycles of docetaxel who developed repeated episodes of hypersensitivity pneumonitis, progressed to respiratory failure and death despite treatment with corticosteroids and supportive care. Docetaxel-induced hypersensitivity pneumonitis was diagnosed by excluding infection and tumor spread with bronchoalveolar lavage and lung biopsy. Physicians should consider such a condition in all patients who present with interstitial pneumonitis and respiratory failure when they are receiving docetaxel and treat them aggressively with steroids and supportive care, as it can be fatal.

Successful desensitization to docetaxel after severe hypersensitivity reactions in two patients.

PURPOSE: Two cases of successful desensitization to docetaxel after severe hypersensitivity reactions are reported. SUMMARY: Two patients with gynecological malignancies (uterine leiomyosarcoma and ovarian adenocarcinoma) experienced severe hypersensitivity reactions with docetaxel, including flushing, numbness, sharp radiating pain, severe nausea and vomiting, apnea, and unresponsiveness. Both patients received ondansetron before docetaxel. One patient received dexamethasone, diphenhydramine, and famotidine premedication before docetaxel, as she had previously reacted to paclitaxel. Docetaxel infusions were stopped, and the reactions were treated with diphenhydramine and dexamethasone (one patient also received famotidine). After resolution of symptoms, the docetaxel was not reinitiated due to the nature of the reactions. For the next cycle, both patients received a graded drug challenge or desensitization. Both were pre-medicated with dexamethasone, diphenhydramine, and famotidine. The docetaxel was given as infusions of 0.1%, 1%, and 10% of the dose, with each infusion given over one hour. After this, the remainder of the dose was infused over one hour. Both patients tolerated this desensitization well and completed a total of three and four cycles each. The first patient to receive the desensitization did complain of chest pain during the first desensitization, and the infusion rate was decreased to administer the drug over two hours. After she tolerated two cycles of two-hour infusions, the infusion rate was increased to administer each docetaxel infusion over one hour. CONCLUSION: Two patients who had severe hypersensitivity reactions to docetaxel successfully received further docetaxel doses via a desensitization procedure that involved the sequential administration of solutions containing increasing concentrations of the drug.

Review of hypersensitivity reactions to antineoplastic agents.

OBJECTIVE: To review the characteristics and management of hypersensitivity reactions caused by antineoplastic agents. METHOD: We conducted a search in the Pubmed and EMBASE databases for the last 10 years. RESULTS: Almost all chemotherapeutic agents have the potential to cause hypersensitivity reactions, but some groups have been associated with increased risk, such as platinum compounds, taxanes, asparaginase, monoclonal antibodies and epipodophyllotoxins. The clinical manifestations of these reactions are variable and unpredictable, including symptoms affecting the skin and the pulmonary, cardiac and gastrointestinal systems. The mechanism associated with their development is not yet fully understood. Diagnosis is based on patients' signs and symptoms and skin testing. The management of patients who suffer a hypersensitivity reaction to a chemotherapeutic agent varies with the severity of the reaction, the need to continue treatment, and the availability of alternative therapies. CONCLUSIONS: Due to a progressive increase in the use of chemotherapeutic agents an increased incidence of hypersensitivity reactions is to be expected. Desensitisation protocols are a noteworthy alternative that make it possible to re-initiate patients' therapy with the causative agent of the hypersensitivity reaction. Their use should be assessed individually, weighing risks and benefits.

Experience with rapid desensitization to chemotherapy in a type B hospital

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