Antibody-Drug Conjugates for Cancer Therapy Hafeez, Umbreen; Parakh, Sagun; Gan, Hui K ...
Molecules (Basel, Switzerland),
10/2020, Letnik:
25, Številka:
20
Journal Article
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Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic ...payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.
Treatment with anti‐programmed cell death protein 1 (PD‐1) antibodies has demonstrated clinical efficacy in a whole range of malignancies including advanced melanoma, renal cell cancer, bladder ...cancer, and non‐small cell lung cancer. Immune‐related adverse events are a unique side effect of checkpoint regulator therapy including anti‐PD‐1 antibodies. Treatment‐related autoimmunity can occur in any organ system, with the median onset usually within 5–15 weeks from the commencement of therapy, depending on the organ system involved. This study describes for the first time a case of delayed autoimmunity occurring 8 months after discontinuing treatment with the anti‐PD‐1 antibody nivolumab in a patient with metastatic melanoma. The case highlights the need for ongoing surveillance of patients treated with immune checkpoint inhibitors even after cessation of therapy, especially as patients increasingly stop treatment after achieving durable responses.
This brief communication reports a case of delayed autoimmune hepatitis that occurred 8 months after discontinuation of nivolumab therapy in a patient with metastatic melanoma.
Radioimmunoconjugates consist of a monoclonal antibody (mAb) linked to a radionuclide. Radioimmunoconjugates as theranostics tools have been in development with success, particularly in hematological ...malignancies, leading to approval by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin's lymphoma. Radioimmunotherapy (RIT) allows for reduced toxicity compared to conventional radiation therapy and enhances the efficacy of mAbs. In addition, using radiolabeled mAbs with imaging methods provides critical information on the pharmacokinetics and pharmacodynamics of therapeutic agents with direct relevance to the optimization of the dose and dosing schedule, real-time antigen quantitation, antigen heterogeneity, and dynamic antigen changes. All of these parameters are critical in predicting treatment responses and identifying patients who are most likely to benefit from treatment. Historically, RITs have been less effective in solid tumors; however, several strategies are being investigated to improve their therapeutic index, including targeting patients with minimal disease burden; using pre-targeting strategies, newer radionuclides, and improved labeling techniques; and using combined modalities and locoregional application. This review provides an overview of the radiolabeled intact antibodies currently in clinical use and those in development.
With the increasing incidence of cancer and related survival, junior doctors are more commonly involved the management of oncology patients. A comprehensive oncology curriculum has been developed and ...adopted across medi-cal schools in Australia. However, it was not designed to inform how medical students should be taught, and whether curriculum content translates to knowledge and competency can depend on its implementation. We have conducted a literature review of PubMed, Embase and Cochrane databases to identify and summarise the evidence for novel approaches to delivering the undergraduate oncology curriculum. Numerous effective approaches have been developed across areas of prevention, clinical examination through simulation, the multidisciplinary team, psycho-oncology, palliative care and even research. There is growing focus on a holistic and multidisciplinary approach to cancer education although direct clinical exposure and interactions with cancer patients is still crucial. Medical schools may also have an under-recognised role in promoting positive health behaviour if their graduates are to convey these preventative measures to their patients. Application of such methods relies upon clinicians and medical educators to consider the practicability and relevance of specific implementation in their local context.
Glioblastoma (GBM) is an aggressive and fatal malignancy that despite decades of trials has limited therapeutic options. Antibody drug conjugates (ADCs) are composed of a monoclonal antibody which ...specifically recognizes a cellular surface antigen linked to a cytotoxic payload. ADCs have demonstrated superior efficacy and/or reduced toxicity in a range of haematological and solid tumors resulting in nine ADCs receiving regulatory approval. ADCs have also been explored in patients with brain tumours but with limited success to date. While earlier generations ADCs in glioma patients have had limited success and high toxicity, newer and improved ADCs characterised by low immunogenicity and more effective payloads have shown promise in a range of tumour types. These newer ADCs have also been tested in glioma patients, however, with mixed results. Factors affecting the effectiveness of ADCs to target the CNS include the blood brain barrier which acts as a physical and biochemical barrier, the pro-cancerogenic and immunosuppressive tumor microenvironment and tumour characteristics like tumour volume and antigen expression. In this paper we review the data regarding the ongoing the development of ADCs in glioma patients as well as potential strategies to overcome these barriers to maximise their therapeutic potential.
In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell ...lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.
IntroductionCancer is predominantly a disease of older adults, with an increasing number of cancer diagnoses in individuals aged 65 or older. Multiple geriatric factors have been shown to impact ...patient outcomes in cancer treatment. However, oncology specialists are not well adapted to incorporate geriatric assessment into practice due to a lack of resources and knowledge of the specialty.The primary aim of this study is to implement and evaluate a nurse-led, multidisciplinary model of care for older adults with cancer at two public tertiary hospitals in Melbourne, Australia.Methods and analysisThis study will aim to assess 200 patients across 2 sites. Both sites will assess individuals with lung cancer; the second site will also include individuals with genitourinary, upper gastrointestinal and colorectal cancers.This process evaluation will use quantitative and qualitative methods to explore the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) of the nurse-led, multidisciplinary model of care.Ethics and disseminationEthical approval and local governance approvals have been obtained by Austin Health and Monash Health Human Research Ethics committees. Dissemination will occur via publications, conferences, social medical and local engagement with clinicians, consumers and managers.
The advent of systemic therapies with high intracranial efficacy in recent years is changing the therapeutic paradigm and renewing interest in the management of central nervous system (CNS) and ...leptomeningeal metastases from solid organ tumors. CNS metastases have traditionally heralded a dismal prognosis with median survival of 3–10 months, and were primarily treated with local therapeutic modalities, such as surgery or radiation therapy. Although these modalities still have a role in the management of CNS disease, newer agents, such as small molecule tyrosine kinase inhibitors and immune‐checkpoint inhibitors, are now paving the way as an alternative therapeutic option for those with oligometastatic or low‐volume intracranial disease, potentially eliminating or delaying the need for local treatment modalities in this setting. Herein, we summarize the systemic treatments with proven intracranial efficacy, currently approved for use in Australia for advanced mutation‐driven non‐small cell lung cancer, melanoma, and breast cancer, as well as novel agents in preclinical and clinical trial development.
Background and Aims
Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience ...of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum‐containing therapy.
Methods
Multicentre real‐world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three‐weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression‐free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA).
Results
Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second‐ (83%, 38/46) or subsequent‐ (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high‐grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six‐month OS was 44% (95% confidence interval (CI): 29.0–57.1). Twelve‐month OS was 15% (95% CI: 6.5–26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8–2.9) and OS was 4.5 months (95% CI: 3.5–7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0–17.2). Individuals with a longer chemotherapy‐free interval prior to lurbinectedin had longer PFS and OS.
Conclusion
This real‐world national experience of lurbinectedin post‐platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.
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