Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune-modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21596

A review of cancer immunotherapy toxicity.

The development of immune-checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease, and providing new therapeutic indications in earlier-stage settings. As such, characterizing the long-term implications of receiving ICIs has grown in importance. An abundance of evidence exists describing the acute clinical toxicities of these agents, although chronic effects have not been as well catalogued. Nonetheless, emerging evidence indicates that persistent toxicities might be more common than initially suggested. While generally low-grade, these chronic sequelae can affect the endocrine, rheumatological, pulmonary, neurological and other organ systems. Fatal toxicities also comprise a diverse set of clinical manifestations and can occur in 0.4–1.2% of patients. This risk is a particularly relevant consideration in light of the possibility of long-term survival. Finally, the effects of immune-checkpoint blockade on a diverse range of immune processes, including atherosclerosis, heart failure, neuroinflammation, obesity and hypertension, have not been characterized but remain an important area of research with potential relevance to cancer survivors. In this Review, we describe the current evidence for chronic immune toxicities and the long-term implications of these effects for patients receiving ICIs. Immune-checkpoint inhibitors (ICIs) have dramatically improved the outcomes of patients with advanced-stage solid tumours, including the potential for long-term remission in a subset. However, long-term follow-up data reveal a risk of chronic toxicities from these agents, which can have important quality-of-life implications. In this Review, the authors describe the current level of evidence of chronic toxicities of ICIs and their implications for patients 

/pdf/immune-checkpoint-inhibitors-long-term-implications-of-11f71ovn.pdf

Immune-checkpoint inhibitors: long-term implications of toxicity

Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.

https://jitc.bmj.com/content/jitc/9/6/e002435.full.pdf

Society for immunotherapy of cancer (sitc) clinical practice guideline on immune checkpoint inhibitor-related adverse events

Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which is called abscopal effect. The view of RT as a simple local treatment has dramatically changed in recent years, and it is now widely accepted that RT can provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy (iRT). Nevertheless, several points remain to be addressed such as the interaction of RT and immune system, the identification of the best schedules for combination with immunotherapy (IO), the expansion of abscopal effect and the mechanism to amplify iRT. To answer these crucial questions, we roundly summarize underlying rationale showing the whole immune landscape in RT and clinical trials to attempt to identify the best schedules of iRT. In consideration of the rarity of abscopal effect, we propose that the occurrence of abscopal effect induced by radiation can be promoted to 100% in view of molecular and genetic level. Furthermore, the "radscopal effect" which refers to using low-dose radiation to reprogram the tumor microenvironment may amplify the occurrence of abscopal effect and overcome the resistance of iRT. Taken together, RT could be regarded as a trigger of systemic antitumor immune response, and with the help of IO can be used as a radical and systemic treatment and be added into current standard regimen of patients with metastatic cancer. 

/pdf/radiotherapy-combined-with-immunotherapy-the-dawn-of-cancer-waf9semi.pdf

Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programed cell death 1 (PD-1), or its ligand (PD-L1) have become the mainstay for advanced malignancies. The incidence of endocrine adverse events provoked by these immune checkpoint inhibitors (ICI) is based on data from randomized controlled trials, which have their drawbacks. PubMed was searched through August 22nd, 2017, by 2 reviewers independently (J.d.F. and C.E.A.). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. The weighted incidence and risk ratio were estimated for hypophysitis, primary thyroid disease, primary adrenal insufficiency, and diabetes mellitus. Their management is discussed in a systematic review. A total of 101 studies involving 19 922 patients were included. Ipilimumab-treated patients experienced hypophysitis in 5.6% (95% CI, 3.9–8.1), which was higher than nivolumab (0.5%; 95% CI, 0.2–1.2) and pembrolizumab (1.1%; 95% CI, 0.5–2.6). PD-1/PD-L1 inhibitors had a higher incidence of thyroid dysfunction – particularly hypothyroidism (nivolumab, 8.0%; 95% CI, 6.4–9.8; pembrolizumab, 8.5%; 95% CI, 7.5–9.7; PD-L1, 5.5%; 95% CI, 4.4–6.8; ipilimumab, 3.8%; 95% CI, 2.6–5.5). Combination therapy was associated with a high incidence of hypothyroidism (10.2–16.4%), hyperthyroidism (9.4–10.4%), hypophysitis (8.8–10.5%), and primary adrenal insufficiency (5.2–7.6%). Diabetes mellitus and primary adrenal insufficiency were less frequent findings on monotherapy. Our meta-analysis shows a high incidence of endocrine adverse events provoked by single agent checkpoint blockade, further reinforced by combined treatment.

/pdf/a-systematic-review-and-meta-analysis-of-endocrine-related-1mtsj4dywt.pdf

A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors.

Normocalcemic primary hyperparathyroidism (NPHPT) is a formally recognized variant of primary hyperparathyroidism (PHPT), characterized by normal total and ionized serum calcium concentrations and elevated parathyroid hormone (PTH) levels, in the absence of secondary causes for hyperparathyroidism. NPHPT has been studied previously, but data are limited and confounded. We aimed to compare the clinical and biochemical data of normocalcemic and hypercalcemic subjects in a hospital-based population. We retrospectively analysed the medical records of 131 subjects diagnosed with PHPT at the university hospital Brussels (UZ Brussel) between January 1st 2007 and December 31st 2016, including 25 normocalcemic and 106 hypercalcemic subjects. The mean values of age, BMI, sex, serum 25-OH vitamin D levels and urinary phosphate excretion were comparable between both groups. Subjects diagnosed with NPHPT had significantly lower plasma PTH levels, lower urinary calcium excretion and lower serum creatinine levels compared to the hypercalcemic subjects with PHPT. Corresponding eGFR values were higher in the normocalcemic group. Normocalcemic subjects (NPHPT) presented with a high prevalence of nephrolithiasis (36%), fragility fractures (12%) and osteoporosis (25%). Clinical manifestations and BMD measurements revealed no statistically significant differences between both groups. Our data show a relative prevalence of 19% NPHPT in PHPT. NPHPT may present the earliest form of PHPT with an extension in time, but is not an indolent disease state. Normocalcemic subjects should be managed as hypercalcemic subjects with PHPT. Further research regarding the pathophysiology and natural course of NPHPT is required.

/pdf/normocalcemic-primary-hyperparathyroidism-a-comparison-with-15y4jod9zb.pdf

Normocalcemic Primary Hyperparathyroidism: A Comparison with the Hypercalcemic Form in a Tertiary Referral Population

A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors

The aim of this study is to assess differences in patient characteristics,
 tumour characteristics and hormone levels between acromegalic patients with
 and without hyperprolactinemia. 44 patients of the University Hospital of
 Brussels, Belgium with acromegaly who were diagnosed between January 2007
 and July 2018 were included in this study. Nineteen patients were classified
 in the hyperprolactinemia group and 25 patients were classified in the
 normoprolactinemia group. No significant differences between acromegalic
 patients with and without hyperprolactinemia were found in age at diagnosis,
 gender, presence of hyperprolactinemia symptoms, insulin-like growth factor
 1, growth hormone and testosterone levels, tumour volume, tumour
 invasiveness, immunohistochemistry of growth hormone and prolactin, Ki-67
 index and mitotic index. However, for a cut-off of 10% of
 prolactin-positive cells, there was a trend towards a higher percentage of
 prolactin-positive tumours in hyperprolactinemia patients (p=0.054)
 and higher mean prolactin level in case of positive prolactin immunostaining
 (p=0.007)). In our study there were no differences in
 characteristics between acromegaly patients with hyper- and
 normoprolactinemia. An association between the serum prolactin level and the
 positivity of prolactin immunohistochemistry of the adenoma tissue was
 found. The absence of a difference in tumour volume between patients with
 hyper- and normoprolactinemia suggests that the hyperprolactinemia is likely
 to be caused by the co-secretion of growth hormone and prolactin by the
 tumour. Finally, for the first time, the cut-off of 10% of prolactin
 cells was validated for the diagnosis of somatolactotroph tumours in
 acromegaly.

/pdf/hyperprolactinemia-in-acromegaly-is-related-to-prolactin-10wmox39ry.pdf

Hyperprolactinemia in Acromegaly is Related to Prolactin Secretion by Somatolactotroph Tumours.

BACKGROUND Differentiated thyroid cancer (DTC) is a common malignancy with increasing incidence. Follow-up care for DTC includes thyroglobulin (Tg) measurement and ultrasound (US) of the neck, combined with 131I remnant ablation when indicated. Diagnostic precision has evolved with the introduction of the new high-sensitive Tg-assays (sensitivity ≤0.1 ng/mL). The aim of the study was to determine the prognostic utility of high-sensitive Tg and the need for other diagnostic tests in DTC. METHODS This was a retrospective, observational study. Patients with pathologically confirmed DTC, treated with total thyroidectomy and 131I remnant ablation, who had their complete follow-up care in our institution were selected (October 2013-December 2018). Subjects with possible thyroglobulin autoantibody interference were excluded. Statistical analysis was performed using the IBM SPSS® Statistics 24 software package. RESULTS Forty patients were eligible for analysis. A total of 24 out of the 40 patients (60%) had an undetectable high-sensitive Tg 6 months after total thyroidectomy. None of these patients had a stimulated Tg above 1 ng/mL, or remnant on the 123I Whole-Body Scan (WBS) after 1 year of follow-up. Ultrasound of the neck, performed between 6 and 12 months postoperative, was negative in 21 out of the 24 patients. CONCLUSIONS This study shows that an undetectable high-sensitive Tg can change the management of patients with DTC and decrease the use and need of stimulated Tg and 123I WBS.

/pdf/undetectable-thyroglobulin-makes-123i-whole-body-scan-and-51wdprbljb.pdf

Undetectable thyroglobulin makes 123I whole-body scan and stimulated thyroglobulin obsolete in follow-up care of differentiated thyroid cancer: a retrospective study.

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