Endogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti–4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency on Fcγ receptor–mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP–4-1BBL (RG7826) and CD19–4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen–mediated hyperclustering without systemic activation by FcγR binding. We could show targeting of FAP–4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer–bearing rhesus monkey. Combination of FAP–4-1BBL with tumor antigen–targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-γ and granzyme B secretion. Further, combination of FAP– or CD19–4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8⁺ T cells. FAP– and CD19–4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies.

Using the ovariectomized macaque model of postmenopausal women's health, we investigated the effects of long-term treatments (5 weeks—3 years) with estradiol, conjugated equine estrogens (CEE), esterified estrogens, progestins such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE + MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative selective estrogen receptor modulators (SERMs), and androgens. Agents tested were selected on the basis of beneficial effects on arteries and/ or bone. Doses were scaled on a caloric or serum-concentration basis to approximate human clinical doses. We evaluated endometrial and mammary gland histopathology and morphometry and used immunohistochemistry to evaluate cell proliferation and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized epithelial proliferation induced by CEE in endometrium and induced pseudodecidual stromal hyperplasia in some animals. Tamoxifen induced endometrial polyps, cystic hyperplasia, stromal fi brosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estrogen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihydroequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in human clinical trials of the same agents.

The authors describe a selection of normal findings and common naturally occurring lesions in the reproductive system of female macaques, including changes in the ovaries, uterus, cervix, vagina, and mammary glands. Normal features of immature ovaries, uteri, and mammary glands are described. Common non-neoplastic lesions in the ovaries include cortical mineralization, polyovular follicles, cysts, ovarian surface epithelial hyperplasia, and ectopic ovarian tissue. Ovarian neoplasms include granulosa cell tumors, teratomas, and ovarian surface epithelial tumors. Common non-neoplastic uterine findings include loss of features of normal cyclicity, abnormal bleeding, adenomyosis, endometriosis, epithelial plaques, and pregnancy-associated vascular remodeling. Hyperplastic and neoplastic lesions of the uterus include endometrial polyps, leiomyomas, and rarely endometrial hyperplasia and endometrial adenocarcinoma. Vaginitis is common. Cervical lesions include endocervical squamous metaplasia, polyps, and papillomavirus-associated lesions. Lesions in the mammary gland are most often proliferative and range from ductal hyperplasia to invasive carcinoma. Challenges to interpretation include the normal or pathologic absence of menstrual cyclicity and the potential misinterpretation of sporadic lesions, such as epithelial plaques or papillomavirus-associated lesions. Interpretation of normal and pathologic findings is best accomplished with knowledge of the life stage, reproductive history, and hormonal status of the animal.Competing Interests: This article was sponsored by Covance Inc. and Schering-Plough. Gerhard F. Weinbauer and Eberhard Buse are employed by Covance Inc. Eveline P. C. T. de Rijk and Eric Van Esch are employed by Schering-Plough. No other competing interests were declared.

To measure the effects of 2 years of treatment with tibolone on the breasts of cynomolgus macaques (Macaca fascicularis) in comparison with conventional hormone replacement therapy. Ovariectomized cynomolgus macaques were randomized into five groups and treated for 2 years. Groups included controls (n = 31) and four drug treatments, including tibolone at 0.05 mg/kg (LoTIB, n = 30) or 0.2 mg/kg (HiTIB, n = 31), conjugated equine estrogens at 0.042 mg/kg (CEE, n = 28), or CEE + medroxyprogesterone acetate (MPA) at 0.167 mg/kg (CEE + MPA, n = 29). Endpoints included histologic, histomorphometric, and immunohistochemical assessment of the mammary gland. Tibolone did not cause stimulation of the breast in contrast to distinct proliferative responses of the breast to CEE and CEE + MPA, as measured by increases in breast epithelial tissue area and expression of the proliferation marker Ki67 in breast epithelial cells. Tibolone at the higher dose increased progesterone receptor expression in the breast relative to controls, indicating partial estrogen-agonist activity, but without induction of proliferation. Progesterone receptor expression was also induced by CEE. Tibolone may have an advantage over conventional hormone replacement therapy because it does not stimulate proliferation in the breast. This lack of mammotrophic effect may reflect a lower risk for promotion of breast cancer.

The complexity of cancer immunotherapy (CIT) demands reliable preclinical models to successfully translate study findings to the clinics. Non-human primates (NHPs; here referring to rhesus and cynomolgus macaques) share broad similarities with humans including physiology, genetic homology, and importantly also immune cell populations, immune regulatory mechanisms, and protein targets for CIT. Furthermore, NHP naturally develop cancers such as colorectal and breast cancer with an incidence, pathology, and age pattern comparable to humans. Thus, these tumor-bearing monkeys (TBMs) have the potential to bridge the experimental gap between early preclinical cancer models and patients with human cancer. This review presents our current knowledge of NHP immunology, the incidence and features of naturally-occurring cancers in NHP, and recent TBM trials investigating CIT to provide a scientific rationale for this unique model for human cancer.