Epigenetic dysregulation has long been recognized as a key factor contributing to tumorigenesis and tumour maintenance that can influence all of the recognized hallmarks of cancer. Despite regulatory ...approvals for the treatment of certain haematological malignancies, the efficacy of the first generation of epigenetic drugs (epi-drugs) in patients with solid tumours has been disappointing; however, successes have now been achieved in selected solid tumour subtypes, thanks to the development of novel compounds and a better understanding of cancer biology that have enabled precision medicine approaches. Several lines of evidence support that, beyond their potential as monotherapies, epigenetic drugs could have important roles in synergy with other anticancer therapies or in reversing acquired therapy resistance. Herein, we review the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other forms of anticancer therapy, including chemotherapy, radiation therapy, hormone therapy, molecularly targeted therapy and immunotherapy. We provide a critical appraisal of the preclinical rationale, completed clinical studies and ongoing clinical trials relating to combination therapies incorporating epi-drugs. Finally, we propose and discuss rational clinical trial designs and drug development strategies, considering key factors including patient selection, tumour biomarker evaluation, drug scheduling and response assessment and study end points, with the aim of optimizing the development of such combinations.
Rationale for anti-OX40 cancer immunotherapy Aspeslagh, Sandrine; Postel-Vinay, Sophie; Rusakiewicz, Sylvie ...
European journal of cancer (1990),
01/2016, Letnik:
52
Journal Article
Recenzirano
Abstract Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune ...responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade –based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials. Accumulating preclinical evidence supports their clinical development. However, conflicting results and controversies between in vitro and in vivo data point to the need for comprehensive ancillary studies to be performed in upcoming clinical trials to better understand the mechanism of action of anti-OX40 mAbs-based therapy.
Objective To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs). Design and methods We report the case of a lung cancer patient with ...diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy. Results Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population. Conclusion ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.
Life expectancy evaluation is crucial when selecting patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on three objective variables (number of ...metastatic sites, lactate dehydrogenase (LDH) and serum albumin) was validated in patients treated with cytotoxics and targeted therapies. We aimed to determine if those factors were applicable to immune-checkpoint therapies (ICTs) in phase I trials and to evaluate new variables that may preclude a better prognosis in patients receiving ICT.
We conducted a retrospective analysis of survival risk factors in a discovery cohort of 155 patients enrolled into ICT phase I trials at our institution. We computed univariate analysis and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in phase I ICT trials was used to prospectively validate this score.
A total of 155 patients (M/F: 83/72; median age 59) receiving an experimental ICT between March 2012 and January 2016 were included in the discovery cohort. An MVA assessing the RMH score variables showed that low albumin (hazard ratio HR 1.73, 95% confidence interval CI 1.05–2.86) and LDH > upper limit normal (ULN) (HR 1.88, 95% CI 1.12–3.15) were independent negative prognostic factors for OS. Interestingly, neutrophil-to-lymphocyte ratio (NLR) > 6 (HR 1.75, 95% CI 1.04–2.95) was associated with a decrease in OS. The number of metastases was not associated with a poorer outcome for this ICT cohort (HR 0.83, 95% CI 0.51–1.35). A risk score based on the results of the MVA (NLR > 6 = 1; LDH > ULN = 1; albumin < 35 g/l = 1) showed that patients presenting a high score (>1) had a significantly shorter OS (20.4 weeks; 95% CI 5.7–35.2) compared to those with a low score (0 or 1) (68.9 weeks; 95% CI 50–83.7) (HR 2.9, 95% CI 1.87–4.64). In the validation cohort of 113 patients, again the patients presenting a high score showed an inferior OS (HR 6.3, 95% CI 2.7–14.8).
In ICT phase I trials, traditional prognostic variables included in the RMH score may be suboptimal to determine patient's prognosis. In this context, the NLR is a significant prognostic variable. The Gustave Roussy Immune Score, based on albumin, LDH and NLR, allows a better selection of patients for ICT phase I trials.
•A prognostic score for patients enrolled in immune phase I trials is purposed.•The GRIm-Score is based on three independent biomarkers: albumin, lactate dehydrogenase and neutrophil-to-lymphocyte ratio.•A prospective validation of the score had been realised.•This score is easily applicable in daily practice.
Anti-PD-(L)1 can provide overall survival (OS) benefits over conventional treatments for patients with many different cancer types. However, the long-term outcome of cancer patients responding to ...these therapies remains unknown. This study is an exploratory study that aimed to describe the long-term survival of patients responding to anti-PD-(L)1 monotherapy across multiple cancer types.
Data from patients treated with an anti-PD-(L)1 monotherapy in a phase I trial at Gustave Roussy were retrospectively analyzed over a period of 5 years. All cancer types (
= 19) were included. Clinical and biological factors associated with response, long-term survival, and secondary refractory disease were studied.
Among 262 eligible patients, the overall objective response rate was 29%. The median progression-free survival of responder patients (RP) at 3 months was 30 months, and the median OS of RP was not reached after a median follow-up of 34 months. In RPs, 3- and 5-year OS percentages were 84% and 64%, respectively. No death occurred in the 21 complete responders (CR) during the overall follow-up. However, many partial responders (PR) showed subsequent tumor relapses to treatment. Long responders (response ≥2 years) represented 11.8% of the overall population. These findings should be validated in further prospective studies.
There are currently no differences in therapeutic strategies between CRs and PRs to anti-PD-(L)1. We found a striking difference in OS between these two types of responses. Our results are in favor of evaluating patient stratification strategies and intensification of treatments when tumor lesions of a partial responder to immunotherapy stop improving.
.
BackgroundWith indications for immune checkpoint inhibitor (ICI) therapy steadily growing, immune related adverse events (irAEs) are increasingly common in the oncologists’ practice. In the absence ...of prospective irAE management trials, the currently existing guidelines on irAE treatment are based on case series, retrospective reviews, and expert opinion. As some of the most lethal irAEs (like pneumonitis, myocarditis, or encephalitis) are rare, multidisciplinary collaboration and discussion is essential. Many countries have responded to this challenge by organizing regional immunotoxicity boards.1 2 Belgium is unique in that it has a nationwide virtual board meeting, serving more than 300 Belgian oncologists.MethodsBITOX is a biweekly virtual meeting between oncologists and organ specialists accessible to all Belgian hospitals.3 Questions regarding diagnosis, management, and prevention of irAEs are submitted online. During the meetings, diagnostic and therapeutic suggestions are made and communicated to the treating physician. The aim is to share experiences, standardize the approach for irAEs and identify clinically relevant research questions.ResultsSince its creation in March 2021, 164 cases were discussed. The majority (n=110; 67%) are questions regarding irAE differential diagnosis and management. Despite their absolute rarity, neurological irAEs are most frequently discussed (n=15; 14%), which stresses the unmet medical need in this area. The other questions (33%) deal with the safety of (re)starting ICI therapy in patients with dysimmune comorbidities. These comorbidities are autoimmune diseases (n=23; 43%), a history of irAE (n=21; 39%), transplant (n=5; 9%) and rarer hematological diseases or paraneoplastic syndromes. We receive questions from university hospitals (n=73; 48%) as well as general hospitals (n=79; 52%) and from both medical oncologists (n=118; 76%) and organ specialists (24%). Cases from 81 different health care practitioners were discussed, concerning patients from 39 different Belgian hospitals on both sides of the language border. Up to 33% of physicians submit a case more than once, illustrating the easy accessibility of the board. We have seen a steady increase in weekly submissions over the last two years with an average of 14 cases per quartile in 2021, 17 in 2022, and 20 in 2023.ConclusionsThe Belgian national multidisciplinary immunotoxicity board aims to harmonize irAE treatment in Belgium. Its unique nationwide reach is an excellent position to identify clinically relevant research questions, which has led to the development of the IMPROVE concept, a prospective irAE management trial framework, with its first trial focusing on immune related pneumonitis treatment expected to start mid 2024.AcknowledgementsWe would like to thank the BSMO immuno taskforce for their valuable and ongoing contributions.ReferencesKennedy LC, Wong KM, Kamat NV, Khaki AR, Bhatia S, Thompson JA, Grivas P. Untangling the Multidisciplinary Care Web: Streamlining Care Through an Immune-Related Adverse Events (IRAE) Tumor Board. Target Oncol. 2020;15(4):541–548.Naidoo J, Zhang J, Lipson EJ, Forde PM, Suresh K, Moseley KF, Mehta S, Kwatra SG, Parian AM, Kim AK, Probasco JC, Rouf R, Thorne JE, Shanbhag S, Riemer J, Shah AA, Pardoll DM, Bingham CO, Brahmer JR, Cappelli LC. A Multidisciplinary Toxicity Team for Cancer Immunotherapy-Related Adverse Events. J Natl Compr Canc Netw. 2019;17(6):712–720.Verhaert M, Aspeslagh S, Bechter O, Wuyts S, Blockx N, Brandao M, Dekervel J, Neyns B, Rutten A, Seront E, Wauters E, Schreuer MS, Drowart A. The Belgian Multidisciplinary Immunotoxicity Board (BITOX): A nationwide initiative of the Belgian Society of Medical Oncology (BSMO). Ann Oncol. 2021;32:S1405.
Background Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are ...limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report. Case We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy. Discussion Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma. Conclusion ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Highlights • No consensus on PD-L1 expression on tumour cells exists in literature. • A more standardised methodology for assessment PD-L1 expression is demanded. • Positive PD-L1 status appears to ...be associated with improved survival in SCCHN. • Further validation of PD-L1 as prognostic/predictive marker in SCCHN is warranted. • Promising novel predictive biomarkers need further validation.
The assessment of tumor infiltrating lymphocytes (TILs) has recently emerged as a prognostic biomarker in several solid tumors. Quantification and subtyping of TILs reflects the immune response in ...the tumor microenvironment, contributing to either tumoral immune attack or escape and thereby affecting outcome. Despite the growing evidence of its value as prognosticator, TILs analysis has not yet found its way to daily clinical practice. The aim of this review is to evaluate whether the current knowledge on TILs in head and neck cancer justifies its clinical implementation. Therefore, we summarize the data on TILs in squamous cell cancer of the head and neck with focus on the most important subsets (T lymphocytes and more specifically CD8
+
cytotoxic T cells and FoxP3
+
regulatory T cells) and site-specific characteristics such as Human Papilloma Virus infection. In addition, we discuss methodological problems and pitfalls that can account for discordant findings and that may hamper inclusion of TILs assessment in routine practice of pathologists and oncologists.
Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in ...13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression.
PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome.
In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination.
EU Clinical Trials Register: EudraCT 2016-001569-97 , registered on 19-6-2017. Clinicaltrials.gov: NCT03192059 , registered on 19-6-2017.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
