Conception and viable twin pregnancy in a patient with metastatic melanoma while treated with CTLA-4 and PD-1 checkpoint inhibition

Abstract

The treatment of cancer during pregnancy presents a unique challenge. Optimal treatments are often altered or even delayed to protect fetal growth and organogenesis. The landscape of cancer treatment has shifted dramatically over the past several years and treatment with checkpoint inhibitors, including anti-PD1 and anti-CTLA-4 agents has revolutionized treatment outcomes for patients across numerous tumor types. Until recently, little is known about the use of checkpoint inhibitor therapy during pregnancy; however, in animal studies, exposure to checkpoint inhibitors at the time of or after conception led to high incidences of spontaneous abortion, stillbirth, and premature delivery. In this report, we describe the successful pregnancy and clinical course of a patient diagnosed with metastatic melanoma who conceived twins while undergoing dual checkpoint blockade with ipilumumab and nivolumab. While there are case reports of patients receiving checkpoint inhibitors during pregnancy, our case is the first to describe a successful pregnancy that was conceived during treatment with combination anti-CTLA-4 and PD-1, with therapy continuing throughout pregnancy. This case adds to the growing evidence that favorable pregnancy outcomes may be possible while receiving checkpoint inhibition, which will hopefully allow for more optimal treatment of young pregnant patients with cancer.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events

“…Additionally, ICI therapy is considered category D in pregnancy, and evidence from solid organ transplant recipients indicates that the risk of fetal malformation is greatly increased if patients are exposed to immunosuppressives such as mycophenolate, 34 35 which are commonly used to manage irAEs. While three isolated case reports have been published of successful pregnancies carried to term while on ICI therapy for metastatic melanoma, [36][37][38] adherence to pregnancy prevention is strongly encouraged during treatment. Managment for irAEs also differs from those for AEs with conventional cancer therapies.…”

Tim‐3/CTLA‐4 pathways regulate decidual immune cells‐extravillous trophoblasts interaction by IL‐4 and IL‐10

“…These results indicated that Tim‐3 and CTLA‐4 pathways regulated maternal‐fetal crosstalk so to play important role in the maintenance of NP. Thus, though it was reported that conception and viable twin pregnancy in a patient with metastatic melanoma while treated with CTLA‐4 and programmed cell death‐1 (PD‐1) checkpoint inhibition, 23 reproductive safety must be considered, especially when these therapies are used during pregnancy.…”

Immune Profile Analysis in Peripheral Blood and Tumor in Patients with Malignant Melanoma

“…Immune checkpoint therapy for pregnancy is well discussed as one of the important problems and requires difficult decisions in both the malignancy carrier's (the mother's) health and the fetus' development. Several cases reported the efficacy of anti-PD-1 antibody treatment during pregnancy without influencing mother and fetus growth [20,21]. However, nivolumab is a human IgG4 monoclonal antibody [22] that easily passes through the placenta and can reach the fetus.…”