Testicular histopathology after immunotherapy for metastatic melanoma.

Benz, Karl; Maruf, Mahir; Duregon, Eleonora; Hooper, Jody E.; Matoso, Andrés; Herati, Amin S.

doi:10.1200/jco.2018.36.15_suppl.e15114

Cited by 8 publications

(4 citation statements)

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“…Preclinical studies of Ipilimumab in monkeys demonstrated a clinically significant decrease in testicular weight, with no evidence of sperm histopathology changes [ 20 ]. A small study assessing testicular histopathology after immunotherapy for metastatic melanoma found evidence that spermatogenesis may be impacted by immunotherapies, however, the mechanism remains unclear [ 23 ]. While it is difficult to calculate fertility risk based on these small studies, there is concern for some level of gonadal dysfunction that needs to be further explored [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Testosterone deficiency in men receiving immunotherapy for malignant melanoma

et al. 2021

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Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.

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Section: Introductionmentioning

confidence: 99%

Testosterone deficiency in men receiving immunotherapy for malignant melanoma

et al. 2021

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“…Corroborating these data was the lack of primordial follicle depletion in settings without the capacity for T-cell infiltration, such as in athymic nude mice which lack T-cell function and reduced inflammation (Pelleitier & Montplaisir 1975, Montgomery et al 2013) and in ovaries cultured in vitro from immunocompetent mice following immunotherapy administration. While a recent clinical study in adult males with metastatic melanoma who were treated with frontline immune checkpoint inhibitor therapy for at least 1 month has revealed impaired spermatogenesis (Benz et al 2018, Scovell et al 2020, Özdemir 2021), the need for further clinical investigation on ovotoxicity from immune checkpoint inhibitors as frontline therapy in female cancer patients remains.…”

Section: Discussionmentioning

confidence: 99%

Effects of PD-1 blockade on ovarian follicles in a prepubertal female mouse

Luan

et al. 2022

Journal of Endocrinology

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Immunotherapy has emerged at the forefront of cancer treatment. Checkpoint inhibitor pembrolizumab (KEYTRUDA), a chimeric antibody which targets programmed cell death protein 1 (PD-1), has been approved by the FDA for use in pediatric patients with relapsed or refractory classical Hodgkin’s lymphoma. However, there is currently no published data regarding the effects of pembrolizumab on the ovary of female pediatric patients. In this study, prepubertal immunocompetent and immunodeficient female mice were injected with pembrolizumab or anti-mouse PD-1 antibody. The number of primordial follicles significantly decreased post-injection of both pembrolizumab and anti-mouse PD-1 antibody in immunocompetent mice. However, no changes in follicle numbers were observed in immunodeficient nude mice. Superovulation test and vaginal opening experiments suggest that there is no difference in the number of COCs and the timing of puberty onset between the control and anti-mouse PD-1 antibody treatment groups, indicating that there is no effect on short-term fertility. Elevation of pro-inflammatory cytokine TNF-α following COX-2 upregulation was observed in the ovary. CD3+ T-cell infiltration was detected within some ovarian follicles and between stromal cells of the ovaries in mice following treatment with anti-mouse PD-1 antibody. Thus, PD-1 immune checkpoint blockade affects the ovarian reserve through a mechanism possibly involving inflammation following CD3+ T-cell infiltration.

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“…While a significant number of patients treated with ipilimumab (11%) suffered from persistent anterior hypophysitis responsible for gonadotropin production, the nivolumab was reported to induce such toxicity in minor (0.5%) number of patients [101,102]. Nevertheless it was also already reported that hypospermatogenesis and aspermatogenesis may represent irAE in selected patients treated with anti-PD1 immunotherapy [103].…”

Section: General Safety Of Nivolumab Treatment In Melanoma Patientsmentioning

confidence: 99%

An update on the safety of nivolumab for the treatment of advanced melanoma

Czarnecka

Rutkowski

2020

Expert Opinion on Drug Safety

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Introduction: Due to its unique mechanism of action as an immune checkpoint inhibitor, nivolumab has high antitumor activity, but at the same time this mechanism is responsible for immune-related adverse events that may limit patients' safety and therapy continuation. Areas covered: Long-term safety of nivolumab including 5-year follow-up, safety of nivolumab treatment after ipilimumab therapy, safety of nivolumab in challenging subgroups (elderly, patients with brain metastases, patients with autoimmune disorders), safety of nivolumab in with rare melanoma subtypes (including mucosal melanoma), as well as specificity of AEs reported for nivolumab treatment in melanoma patients in comparison to other cancer types and other immunotherapy molecules, and impact of AEs on response rates and PFS on nivolumab treatment are discussed. Expert opinion: Search for biomarkers that would help us to identify patient populations that may suffer from severe nivolumab toxicity could help in selecting patients that should not be treated with this type of therapy. Novel combinations and immunotherapy drugs including use of NKTR-214 (IL-2 pathway), lymphocyte-activation gene 3 (LAG-3), local injections of talimogene laherparepvec (T-VEC), or systemic use of T-cell receptors agonists such as OX40, CD137, ICOS-1, could provide regimens with limited toxicity and higher activity.

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Testicular histopathology after immunotherapy for metastatic melanoma.

Cited by 8 publications

References 0 publications

Testosterone deficiency in men receiving immunotherapy for malignant melanoma

Testosterone deficiency in men receiving immunotherapy for malignant melanoma

Effects of PD-1 blockade on ovarian follicles in a prepubertal female mouse

An update on the safety of nivolumab for the treatment of advanced melanoma

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