In vivo tracking of macrophage activated killer cells to sites of metastatic ovarian carcinoma

Abstract

Radio-labelling of blood cells is an established technique for evaluating in vivo migration of normal cells to sites of pathology such as infection and haemorrhage. A limitation of cellular immunotherapies to induce anti-tumour responses is in part due to the uncertain ability of cellular effectors to reach their intended target. We extended the approach of cell radiolabelling to accurately examine the in vivo distribution of cellular immunotherapy with ex-vivo macrophage activated killer (MAK) cells. We describe the use of two methods of cell labelling for tracking the destination of autologous-derived macrophage activated killer (MAK) cells linked to the bi-specific antibody MDX-H210 delivered either by intravenous (i.v.) or intraperitoneal (i.p.) injection in ten patients with peritoneal relapse of epithelial ovarian carcinoma. Our results demonstrate the feasibility of generating high numbers and purity of GMP quality MAK cells, which can be radiolabelled with (18)F-FDG or (111)In-oxime. MAK cell administration produced minimal infusional toxicity and demonstrated a reproducible pattern of in vivo distribution and active in vivo tracking to sites of known tumour following 8 of 16 i.v. infusions or 4 of 6 i.p. infusions. However, the leakage of (18)F-FDG limited the ability to confidently confirm the tracking of MAK cells to tumour in all cases and improved PET labels are required. The addition of MDX-H210 bispecific antibody did not alter the distribution of cells to tumour sites, but did accelerate the clearance of i.v. administered MAK cells from the pulmonary circulation. This data demonstrates that cellular cancer immunotherapies may be successfully delivered to the sites of active tumour following either i.v. or i.p. injection in a proportion of patients with metastatic cancer. Incorporation of tracking studies in early cycles of cellular immunotherapy may allow selection of patients who demonstrate successful targeting of the immunotherapy for ongoing treatment.

Immune Response in Ovarian Cancer: How Is the Immune SystemInvolved in Prognosis and Therapy: Potential for Treatment Utilization

“…MAK cells have been used as a form of adoptive immunotherapy alone or in combination with monoclonal antibodies [58, 169, 170]. MAK can reach tumor sites by intraperitoneal infusion, but most studies are small and the role of this approach remains undetermined.…”

Brain ingress of regulatory T cells in a murine model of HIV-1 encephalitis☆

“…This contrasts significantly to the brain; wherein, Treg infiltrated HIVE affected brain regions and were retained in sites of viral-induced inflammation. This seemingly paradoxical result between the imaging data and immunohistochemical evaluations likely reflected increased leakage of radiolabel from the adoptively-transferred Treg that have been noted in other replicate systems (Botti et al, 1997; Kuyama et al, 1997; Ritchie et al, 2007). …”

Macrophage-based cell therapies: The long and winding road

“…Other trials infused the MΦs directly into the tumor location including intraperitoneal injections in patients with metastatic lesions in the peritoneum [53, 62] and intravesically into the bladder of bladder cancer patients [63, 64]. Initial trial results in treatment of bladder cancer were positive enough to warrant further comparative trials against standard therapies [63]. However, MΦ instillations were not nearly as effective as the standard therapy in the bladder [64].…”