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Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.

ABSTRACT: The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I-III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity.

SUBMITTER: Brown JS

PROVIDER: S-EPMC5808021 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.

Brown Jessica S JS Sundar Raghav R Lopez Juanita J

British journal of cancer 20171109 3

The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby act ...[more]

PMID: 29123260

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Project description:Dietary studies can reveal valuable information on how species exploit their habitats and are of particular importance for insular endemics conservation as these species present higher risk of extinction. Reptiles are often neglected in island systems, principally the ones inhabiting remote areas, therefore little is known on their ecological networks. The Selvagens gecko Tarentola (boettgeri) bischoffi, endemic to the remote and integral reserve of Selvagens Archipelago, is classified as Vulnerable by the Portuguese Red Data Book. Little is known about this gecko's ecology and dietary habits, but it is assumed to be exclusively insectivorous. The diet of the continental Tarentola species was already studied using classical methods. Only two studies have used next-generation sequencing (NGS) techniques for this genus thus far, and very few NGS studies have been employed for reptiles in general. Considering the lack of information on its diet and the conservation interest of the Selvagens gecko, we used morphological and DNA metabarcoding approaches to characterize its diet. The traditional method of morphological identification of prey remains in faecal pellets collected over a longer period was compared with metabarcoding of samples collected during rapid surveys. Molecular results revealed that this species is a generalist, feeding on invertebrate, plant and vertebrate items, whereas the morphological approaches were unable to detect the latter two. These results opened up new questions on the ecological role of the Selvagens gecko that deserves to be further explored, such as the possible predation on seabirds, plant services or trophic competition with the sympatric Madeira lizard Teira dugesii. Metabarcoding identified a greater diversity of dietary items at higher taxonomic resolution, but morphological identification enabled calculation of relative abundances and biomasses of ingested arthropods, and detected a dietary shift on invertebrate preys between seasons. Results of this study highlight the global applicability of rapid metabarcoding surveys for understudied taxa on remote islands that are difficult to access. We recommend using the metabarcoding approach, even if 'speedy' sampling only is possible, but we must highlight that disregarding long-term ecological data may lead to 'hasty' conclusion.

Project description:Implantable chemoport is a very useful device for long-term venous access for infusion of chemotherapeutic drugs and other agents. There are few studies from resource poor countries reporting complications of chemoport. The aim of the present study is to evaluate the feasibility of chemoport insertion without image guidance and by closed technique without direct visualisation of a major vein (mainly IJV) and to study the complications associated with the procedure. This was a prospective observational study which analysed 263 patients who underwent chemoport insertion. The medical records of these patients were analysed for the patient characteristics, diagnosis, port-related complications, and their management. A total of 263 patients who were harbouring either locoregionally advanced or metastatic tumour requiring either chemotherapy or targeted treatment or both were included in the study. In total, 133 (50.57%) were female patients and 130 were male patients (49.43%). A total of 236 patients (89.73%) underwent port insertion procedures under local anaesthesia. None of the patients had any major intra-operative complications. Postoperatively, 4 patients (1.52%) were found to have port catheter malposition; 3 out of this 4 were corrected under IITV guidance as a second procedure under local anaesthesia only. One patient (0.38%) required formal removal and replacement of port. Four patients (1.52%) developed IJV thrombosis requiring port removal and anti-coagulation. One patient (0.38%) developed thrombus in the right atrium. There were 2 port site infections (0.74%) requiring port removal (SSI cat. 5). Low complication rates of port insertion were observed in the present, large, prospective study. Complication rates may be further reduced by using a well-designed procedure, experienced surgeons, an aseptic environment, ultrasound-guided puncture, and fluoroscopy with contrast media.Supplementary informationThe online version contains supplementary material available at 10.1007/s13193-020-01265-6.

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Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.

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Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.

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