The future of affordable cancer immunotherapy

The treatment of cancer was revolutionized within the last two decades by utilizing the mechanism of the immune system against malignant tissue in so-called cancer immunotherapy. Two main developments boosted cancer immunotherapy: 1) the use of checkpoint inhibitors, which are characterized by a relatively high response rate mainly in solid tumors; however, at the cost of serious side effects, and 2) the use of chimeric antigen receptor (CAR)-T cells, which were shown to be very efficient in the treatment of hematologic malignancies, but failed to show high clinical effectiveness in solid tumors until now. In addition, active immunization against individual tumors is emerging, and the first products have reached clinical approval. These new treatment options are very cost-intensive and are not financially compensated by health insurance in many countries. Hence, strategies must be developed to make cancer immunotherapy affordable and to improve the cost-benefit ratio. In this review, we discuss the following strategies: 1) to leverage the antigenicity of “cold tumors” with affordable reagents, 2) to use microbiome-based products as markers or therapeutics, 3) to apply measures that make adoptive cell therapy (ACT) cheaper, e.g., the use of off-the-shelf products, 4) to use immunotherapies that offer cheaper platforms, such as RNA- or peptide-based vaccines and vaccines that use shared or common antigens instead of highly personal antigens, 5) to use a small set of predictive biomarkers instead of the “sequence everything” approach, and 6) to explore affordable immunohistochemistry markers that may direct individual therapies

Long-term real-world experience with ipilimumab and non-ipilimumab therapies in advanced melanoma: the IMAGE study.

Funder: This work was supported by Bristol Myers Squibb (no grant number is applicable).BACKGROUND: Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies. METHODS: IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed. RESULTS: Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti-programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab-treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab-treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy (IPI-noOther and Other-Other) showed similar OS. In treatment-naive patients, those in the IPI-noOther group tended to have longer OS than those in the Other-Other group. Patient-reported outcomes were similar between treatment cohorts. CONCLUSIONS: With long-term follow-up (≥ 3 years), safety and OS in this real-world population of patients treated with ipilimumab 3 mg/kg were consistent with those reported in clinical trials. Patient-reported quality of life was maintained over the study period. OS analysis across both pretreated and treatment-naive patients suggested a beneficial role of ipilimumab early in treatment. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01511913. Registered January 19, 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01511913

Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma

Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.

Functional and regulatory profiling of energy metabolism in fission yeast

Background: The control of energy metabolism is fundamental for cell growth and function and anomalies in it are implicated in complex diseases and ageing. Metabolism in yeast cells can be manipulated by supplying different carbon sources: yeast grown on glucose rapidly proliferates by fermentation, analogous to tumour cells growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration. Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth. Growth media and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the mutant screens have not been implicated in respiration in budding yeast. We applied gene-expression profiling approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to respiratory growth. The transcript levels of most genes functioning in energy metabolism pathways are coherently tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that acetyl-CoA synthase, rather than citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from mitochondrial malfunction. Conclusions: This study provides a rich framework of the genetic and regulatory basis of energy metabolism in fission yeast and beyond, and it pinpoints weaknesses of commonly used auxotroph mutants for investigating metabolism. As a model for cellular energy regulation, fission yeast provides an attractive and complementary system to budding yeast

A New Role of Vemurafenib as a Neoadjuvant Treatment of Axillary and Brain Melanoma Metastases

Vemurafenib is approved by the FDA for the management of unresectable or metastatic melanoma. However, its role as a neoadjuvant therapy has not been determined. We present the first documented case in which vemurafenib induced complete tumor necrosis of both lymph node and brain metastases within one month or less, an outcome that indicated that the patient was a good candidate for excisional surgery

Constructive Anthropomorphism: Electronic Supplementary Materials from Constructive anthropomorphism: a functional evolutionary approach to the study of human-like cognitive mechanisms in animals

Anthropomorphism, the attribution of human cognitive processes and emotional states to animals, is commonly viewed as non-scientific and potentially misleading. This is mainly because apparent similarity to humans can usually be explained by alternative, simpler mechanisms in animals, and because there is no explanatory power in analogies to human phenomena when these phenomena are not well understood. Yet, because it is also difficult to preclude real similarity and continuity in the evolution of humans' and animals’ cognitive abilities, it may not be productive to completely ignore our understanding of human behaviour when thinking about animals. Here we propose that in applying a functional approach to the evolution of cognitive mechanisms, human cognition may be used to broaden our theoretical thinking and to generate testable hypotheses. Our goal is not to ‘elevate’ animals, but rather to find the minimal set of mechanistic principles that may explain ‘advanced’ cognitive abilities in humans, and consider under what conditions these mechanisms were likely to enhance fitness and to evolve in animals. We illustrate this approach, from relatively simple emotional states, to more advanced mechanisms, involved in planning and decision-making, episodic memory, metacognition, theory of mind, and consciousness

Recombination and the evolution of coordinated phenotypic expression in a frequency-dependent game

A long standing question in evolutionary biology concerns the maintenance of adaptive combinations of traits in the presence of recombination. This problem may be solved if positive epistasis selects for reducing the rate of recombination between such traits, but this requires sufficiently strong epistasis. Here we use a model that we developed previously to analyze a frequency-dependent strategy game in asexual populations, to study how adaptive combinations of traits may be maintained in the presence of recombination when epistasis is too weak to select for genetic linkage. Previously, in the asexual case, our model demonstrated the evolution of adaptive associations between social foraging strategies and learning rules. We verify that these adaptive associations, which are represented by different two-locus haplotypes, can easily be broken by genetic recombination. We also confirm that a modifier allele that reduces the rate of recombination fails to evolve (due to weak epistasis). However, we find that under the same conditions of weak epistasis, there is an alternative mechanism that allows association between traits to evolve. This is based on a genetic switch that responds to the presence of one social foraging allele by activating one of two alternative learning alleles that are carried by all individuals. We suggest that such coordinated phenotypic expression by genetic switches offers a general and robust mechanism for the evolution of adaptive combinations of traits in the presence of recombination

Evolution of social learning when high expected payoffs are associated with high risk of failure

In an environment where the availability of resources sought by a forager varies greatly, individual foraging is likely to be associated with a high risk of failure. Foragers that learn where the best sources of food are located are likely to develop risk aversion, causing them to avoid the patches that are in fact the best; the result is sub-optimal behaviour. Yet, foragers living in a group may not only learn by themselves, but also by observing others. Using evolutionary agent-based computer simulations of a social foraging game, we show that in an environment where the most productive resources occur with the lowest probability, socially acquired information is strongly favoured over individual experience. While social learning is usually regarded as beneficial because it filters out maladaptive behaviours, the advantage of social learning in a risky environment stems from the fact that it allows risk aversion to be circumvented and the best food source to be revisited despite repeated failures. Our results demonstrate that the consequences of individual risk aversion may be better understood within a social context and suggest one possible explanation for the strong preference for social information over individual experience often observed in both humans and animals