Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy.

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.

Cutaneous lymphosarcoma in a double yellow-headed Amazon parrot (Amazona ochrocephala oratrix).

A 2-year-old double yellow-headed Amazon parrot (Amazona ochrocephala oratrix) was presented for evaluation of a mass on the left wing. A second soft tissue swelling was present under the left mandible and a third in the right inguinal region. The bird had pale mucous membranes, but no other abnormalities were observed on physical examination. Results of the complete blood count and plasma biochemical profile were anemia and decreased total solids. Cytologic findings from fine needle aspirates of the 3 affected areas were nondiagnostic. Whole-body radiographs revealed focal soft tissue swellings. Doppler ultrasound demonstrated significant vascularity in the inguinal swelling; therefore, biopsy of the area was considered contraindicated. Because of the rapid and extensive progression of disease, the owners elected euthanasia. Gross postmortem examination revealed marked and generalized skin thickening. The spleen was slightly enlarged and the bone marrow prominent and gelatinous. The histologic diagnosis was lymphosarcoma, which involved the skin, spleen, and bone marrow. Immunohistochemistry results were consistent with lymphosarcoma of T-cell origin. This case presents an unusual cutaneous manifestation of lymphosarcoma in an Amazon parrot.

Correction of angular limb deformity in two subspecies of flamingo (Phoenicopterus ruber) utilizing a transphyseal bridging technique.

Three hand-raised American flamingo (Phoenicopterus ruber ruber) chicks and one hand-raised Chilean flamingo (Phoenicopterus ruber chilensis) developed valgus angular limb deformities of the proximal tarsometatarsal bone. All flamingos underwent surgical correction to unequally retard the growth plate using transphyseal bridging. Positive profile pins were placed in the proximal epiphysis and distal to the growth plate in the metaphysis on the convex side of the affected tarsometatarsus. Various banding techniques were used in each flamingo to create tension. Three of the four flamingos responded in 7-14 days with correction or slight overcorrection of the valgus limb deformity. The fourth flamingo's leg deformity did not improve for reasons thought to be related to improper implant placement. Growth plate retardation by transphyseal bridging proved successful in correcting valgus limb deformity of the proximal tarsometatarsus. This technique may be considered as an option for correction of angular limb deformities of the proximal tarsometatarsus in flamingos less than 90-120 days of age.

Zoonotic diseases of primates.

A zoonotic disease is transmissible from vertebrate animals to humans. This article focuses on pertinent zoonotic diseases that have to be taken into consideration when working with nonhuman primate (NHP) species. Many factors may influence the occurrence of these diseases. Human and NHPs share many similarities, not only anatomically but also physiologically. NHP are valuable models for many human infectious diseases; therefore, staff can be exposed to many potential pathogens. In general, the disease state of a primate can range from asymptomatic carrier to death from infection.

Avian renal system: clinical implications.

The avian renal system differs anatomically and physiologically from the mammalian renal system. However, it is affected by similar disease categories such as infectious, nutritional, degenerative, congenital, metabolic, and neoplastic conditions. The diagnosis of renal disease in birds can be challenging and, in many cases, diagnosis is made on postmortem examination. Successful treatment of avian renal disease requires early recognition of clinical signs and correct interpretation of diagnostic tools.