Advance-CTR

Advance RI-CTR Pilot Projects Program (Cycle 7)

"Effects of In Utero Exposure to Immunotherapy Treatment on the Developing Ovarian Reserve and Fertility Potential"

As more women delay child-bearing, the incidence of cancer diagnosis during pregnancy is also on the 
rise, necessitating treatments which are beneficial to the mother while also balancing the health of the 
fetus. While short-term studies on exposed children have been performed, the long-term effects of 
exposure to conventional and emerging cancer treatments are lacking. Dr. Grive's study will explore the 
long-term endocrine and reproductive effects on daughters exposed to specific agents during gestation 
with the goal of better understanding how to mitigate detrimental effects.

Maternal malignancy complicates approximately 1 in 1000 pregnancies and the incidence is increasing as maternal age increases. Treatment for these diseases must balance the health of the  mother as well as that of the developing fetus. Currently, many conventional chemotherapies have been  deemed safe for use in the second and third trimesters based on short-term fetal outcomes, though  long-term studies on exposed children are lacking. One of the major initiatives in my laboratory is to  understand the long-term fertility effects of in utero exposure to chemotherapy, as postnatal exposure to  many chemotherapies is known to result in ovarian injury and infertility, ultimately impacting a woman’s  quality of life and even her longevity. In my lab, we have found transgenerational effects on ovarian  function as a result of exposure to in utero exposure to commonly-utilized chemotherapies for maternal  malignancy. This proposal aims to explore the long-term reproductive effects of in utero exposure to  emerging immunotherapies, treatments which are on the forefront of clinical practice for cancer treatment.  Many immunotherapies show tremendous promise as maintenance therapies, or in treatment regimens  with dose-reduced chemotherapies, potentially allowing for cancer treatment with few systemic and  reproductive side effects. However, the effects of these therapies on in utero-exposed daughters is 
currently entirely unknown. 

We hypothesize that immunotherapy will be less toxic to the ovary than traditional chemotherapies,  and will therefore not cause long-term effects on ovarian architecture, oocyte density, estrus cycling or  fertility and fecundity compared to control animals. Using our mouse model of pregnancy, mice will be  treated with a single dose of monoclonal antibody at a specific developmental time point in late-gestation  (anti-VEGF, a Bevacizumab biosimilar , or anti-CTLA4, an Ipilimumab biosimilar), while control pregnant mice will be administered an identical concentration of negative controls IgG isotype control or saline, or the positive control, Docetaxel. In specific aim 1, pups exposed in utero will be assessed for ovarian health at both pre- and post-sexual maturity. In specific aim 2, additional exposed pups will be aged to reproductive maturity and then assessed for reproductive potential by profiling their estrus cycles and their fecundity compared to control mice. This study will elucidate the potential long-term fertility effects due to in utero exposure to targeted- and immuno-therapies for maternal malignancy.

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