Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis

Abstract

Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM. IP delivery of CAR-T cells has shown demonstrable suppression of tumors expressing carcinoembryonic antigen. This response was enhanced when IP injected CAR-T cells were combined with anti-PD-L1 or anti-Gr1. Similarly, CAR-T cells against folate receptor α expressing tumors improved T-cell tumor localization and survival when combined with CD137 co-stimulatory signaling. Moreover, IP immunotherapy with catumaxomab, a trifunctional antibody approved in Europe, targets epithelial cell adhesion molecule (EpCAM) and has shown considerable promise with control of malignant ascites. Herein, we discuss immunologic approaches under investigation for treatment of PM.

Keywords: CAR-T cells; ascites; carcinoembryonic antigen; dendritic cells; folate receptor α; intraperitoneal immunotherapy; metastasis; peritoneal; vaccines.

Figure 1

(A) Abdominal peritoneal metastasis from ovarian cancer. White arrows demonstrate peritoneal disease (Permission granted by Scott D Richard). (B) Coronal CT-scan of the abdomen and pelvis depicting extensive peritoneal metastasis and tumor burden from appendiceal cancer. White arrow demonstrates extensive intraperitoneal disease.

Figure 2

T cells are expanded from peripheral blood mononuclear cells (PBMCs) and transduced with a vector containing the chimeric antigen receptor (CAR) gene. T cells expressing CARs (CAR-T cells) specific for tumor-associated antigens (TAAs) are delivered to the patient intraperitoneally to maximize delivery to the site of disease while minimizing systemic exposure and toxicity.

Figure 3

Dendritic cells (DCs) derived from the isolated patient peripheral blood mononuclear cells (PBMCs) are cultured with tumor-associated antigen(s) (TAA) of interest which can be from whole tumor cells, recombinant virus with tumor antigen DNA or peptide-pulsed. The efficiency of anti-tumor activity is further enhanced when DCs are delivered in combination with natural killer cells (NKs), cytokine-induced killer cells (CIKs) and inhibitors of immune checkpoints (anti CTLA-4 and anti PD-1/PDL-1). Another strategy involves in vitro expansion and IP delivery of CD4⁺ T helper cells.

Figure 4

Catumaxomab, a trifunctional antibody contains three important binding sites: One site binds to the epithelial cell adhesion molecule (EpCAM) overexpressed on tumor cells and the second site binds to CD3⁺ T cells. This bispecific antigen binding leads to apoptotic tumor lysis and the resulting apoptotic bodies are phagocytosed. The third binding domain is fragment crystallizable (Fc) which binds to types I, IIa, and III Fcγ-receptors on dendritic cells (DCs), natural killer cells (NKs) and macrophages leading to direct phagocytosis of tumor cells . Furthermore, Fc binding to accessory cells leads to the release of cytotoxic/ pro-apoptotic cytokines.