Immunotherapy for Peritoneal Carcinomatosis: History
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Contributor:
Mefotse Saha Cyrelle Ornella
,
Narayanasamy Badrinath
,
Kyeong-Ae Kim
,
Jung Hee Kim
,
Euna Cho
,
Tae-Ho Hwang
,
Jae-Joon Kim

Peritoneal carcinomatosis is a challenging condition that affects many cancer patients, and conventional therapies have limited efficacy in treating it. However, recent advances in the field of immunotherapy have shown promise in improving treatment outcomes. One promising approach is immune checkpoint inhibitors, which block proteins that inhibit T-cell activity and promote an anti-tumor immune response. Another approach involves the use of CAR-T cells, which are genetically modified T cells engineered to recognize and target cancer cells expressing specific antigens. In addition, dendritic cells and vaccine-based therapeutics are also designed to stimulate the immune system to recognize and attack cancer cells.

  • intraperitoneal immunotherapy
  • peritoneal carcinomatosis
  • ascites

1. Introduction

Peritoneal carcinomatosis (PC), a fatal tumor diagnosis, often has a dismal prognosis. PC is the metastatic involvement of the peritoneum, the thin membrane that encircles abdominal organs [1][2]. In gastrointestinal (e.g., colorectal and gastric cancers) and gynecological (e.g., ovarian cancer) malignancies, the average survival time for PC is less than six months [3][4][5][6][7]. PC occurs in around 15% of colorectal cancer patients [2] and up to 50% of patients with recurrent gastric cancer [8]. Patients with PC have limited therapeutic options. The specific etiology of the ailment is unknown, and the optimal target has not yet been identified. Palliative systemic treatment is the first line of therapy since a full surgical intervention is tricky and often results in an increase in morbidity and death [9]. Chemotherapy or other types of permitted systemic therapy are typically insufficient for peritoneal dissemination. This is due to restricted drug delivery and adverse effects that include intestinal obstruction and abdominal bloating. Multiple studies have demonstrated that PC patients who have cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), especially when full cytoreduction is achievable, have a higher survival rate [10][11][12]. However, the majority of clinical research on peritoneal surface cancers is hindered by chronically high recurrence rates and poor patient survival [13]. Most patients have extensive peritoneal metastases and severe disease, and the location of the tumor growth on the peritoneal layer inside the abdominal area is one of the characteristics that separate PC from distant metastases. Consequently, locoregional treatment alternatives are likely more suited for treating PC. In response to the difficulties presented by PC in understanding genetics and the formation of cancer, the value of cutting-edge tools such as RNA sequencing and cytometry has grown [14][15].
Immunotherapy has emerged as a promising treatment approach for PC. The peritoneal cavity contains a variety of immune cells, and recent research has shown that the immune system plays an important role in controlling tumor growth in the peritoneum. However, tumors in the peritoneum often develop

2. Peritoneal Carcinomatosis

2.1. Peritoneum and Peritoneal Carcinomatosis

One of the most active tissues in the human body is the peritoneum, often known as the surface tissue of the peritoneal cavity. Immunological mechanisms are most likely to manifest in individuals with local or diffuse peritonitis caused by any bacterial infection. The peritoneum has several transport systems, substantial microcirculation, and substantial blood flow. It is an important barrier that prevents intra-abdominal diseases from spreading throughout the body [16]. A multistep procedure that leads to the development of PC begins with the separation of malignant cells from the early tumors. The detached cells then attach themselves to peritoneal mesothelial cells, causing these cells to shrink and expose the basement membrane. The cancerous cells then multiply and form a cluster, which triggers the process of angiogenesis. The newly formed cluster, along with the blood vessels surrounding the tumor, supports the growth of the tumor, as shown in Figure 1 [17].
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Figure 1. The development of peritoneal carcinomatosis: (a) The cancer cells dissociate from the main tumor and (b) penetrate the epithelial tissue. Cancer cells that have exfoliated invade the underlying basal lamina and stroma. (c) Stromal cancer cells defy apoptosis and entice growth substances that stimulate proliferation and angiogenesis. (d) After breaking through the endothelial cells that border the vessels, cancer cells spread to other parts of the body. (e) Blood vessels in close proximity to a tumor facilitate the development of distant metastases. (f) At a future metastatic site, cancer cells adhere to and invade the endothelium to form a new metastasis.
Primary and secondary PC are two forms of this cancer that can appear on the peritoneal surface. Cancer of the peritoneum and mesothelioma of the peritoneum are the most prevalent types of primary peritoneal tumors. Secondary tumors in the peritoneum include those of the digestive tract and the gynecological system, to name just two. PC has traditionally been considered a kind of systemic and extensive metastasis, as well as the ultimate stage of illness for which only palliative treatment is warranted [18].
However, in its earliest stages, the disease may cause no symptoms at all. Ascites or intestinal obstruction are common early symptoms, which often indicate a more advanced stage of the illness with a larger tumor load that is more challenging to cure [19]. Detecting PC early, while there is still just a small amount of tumor, may improve the success rate of existing treatments [20].
The use of CRS followed by HIPEC (CRS-HIPEC) has shown some effectiveness, but only in a few patients with light disease loads. All detectable intraperitoneal (IP) tumors are removed with CRS-HIPEC, and any remaining microscopic disease is treated with chemotherapy administered locally. Compared to systemic chemotherapy, individuals with CRC PC who had CRS-HIPEC had a considerably higher 5-year survival rate [12][21].

2.2. Immune Environment of Peritoneal Carcinomatosis

The innate (neutrophils, macrophages, dendritic cells, and natural killer cells) and the adaptive (B and T lymphocytes) immune systems can recognize and destroy tumor cells. However, cancer cells gain the ability to evade immune surveillance by targeting or manipulating the immune system. Since lymph nodes and the greater omentum both include immune cells such as macrophages and lymphocytes, immune cell activation may be a potential PC treatment strategy [22]. The peritoneal cavity has immunologically competent cells, such as 45% of monocytes/macrophages (CD68+), 45% of T-lymphocytes (CD2+), 8% of NK-cells (natural killer cells), and 2% of dendritic cells, as well as A substantial proportion of CD4+ (92%) and CD8+ (73%). Approximately 49% of the cells in the peritoneum were positive for class II major histocompatibility complex antigens [23]. In contrast to CD45RO-naive T-lymphocytes, CD45RO+ T-lymphocytes have already differentiated into memory and effector T cells. In contrast to peripheral blood cells, which have a predominance of CD8+ T-lymphocytes, healthy individuals have an inverted CD4+/CD8+ T-lymphocyte ratio. Innate immunity is activated by mesenchymal precursors of the peritoneum. Interleukin-1 (IL-1), interleukin-6 (IL-6), prostaglandin E2, granulocyte stimulating factor (GCSF), granulocyte monocyte colony-stimulating factor (GM-CSF), monocyte colony-stimulating factor (MCSF), and vascular epithelial growth factor (VEGF) are all pro-inflammatory mediators that are released by mesenchymal cells. Figure 2 shows the cell ascites tumor microenvironment (TME).
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Figure 2. Cells in the ascites tumor microenvironment (TME). The peritoneal carcinomatosis microenvironment is formed of malignant ascites and solid tumor tissue. Under the influence of the ascites, which exchange O2 and nutrients with the circulatory system, cells actively communicate with each other through molecules they produce (cytokines, chemokines, DAMPs, etc.) and receptors they express (MHC, PD-1). The TME may re-polarize the same set of cells or move cell components to other locations. The growth or shrinkage of a tumor site is controlled by a complex network of cells and molecules in the TME.
In vitro experiments revealed that, in response to interferon-gamma stimulation, peritoneal mesothelial cells express HLA-DR and ICAM-1 molecules. These findings demonstrate that antigen presentation to T cells is more potent than previously believed, hence promoting the proliferation of T cells driven by anti-CD3. The production of interleukin-2 (IL-2), interleukin-15 (IL-15), and interferon-gamma indicate the presence of a favorable cytokine environment. In this regard, it has been proposed that stimulating the innate immune system is an effective therapy for peritoneal dissemination. This may be accomplished with dendritic cells. Because they are antigen-presenting cells, they might be used as therapeutic vaccines in co-culture with autologous T lymphocytes to educate and stimulate specific antitumor lymphocytes [24].
The tumor immune microenvironment (TME) of PM lesions in gastric cancer is different from primary lesions. Fujimori et al. described that the PM tumor is an enriched desmoid (fibrous) component induced by CAFs and the number of CD8 positive cells was significantly lower in PM lesions than in primary lesions. Conversely, the number of CD163 positive cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions. Therefore, PM mouse models should be used and established similar to the TME of human clinical PM in gastric cancer by using YTN16 and LmcMF [25].
Immunotherapy is generally known to be less effective in PC due to the characteristics of immunologic change, such as an immunosuppressive environment created by the tumor, which hinders the activation of immune cells against cancer cells [26][27][28][29]. 

3. Immune Checkpoint Inhibitors

Patients with a wide variety of cancers benefit from antibodies that target immunological checkpoints, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), PD-1, and PD-L1 [30]. In 2011, for the first time, the FDA approved ipilimumab as an immune checkpoint inhibitor (ICI) for the treatment of metastatic melanoma [31].
ICI has shown excellent and, most importantly, long-lasting responses in advanced tumor patients, unlike targeted treatment and chemotherapy. It is known that factors such as microsatellite instability (MSI-H), tumor mutation burden (TMB), and PD-L1 expression can be used to predict the therapeutic response of an ICI [32]. However, there is still insufficient evidence on whether these factors have a therapeutic effect in peritoneal metastasis. MSI-H cancers occur in gastrointestinal (colorectal, gastric, hepato-biliary) and endometrial malignancies and are caused by germline mutations in one of the DNA mismatch repair genes or somatic promoter hypermethylation of MLH. A high tumor mutation load boosts immunogenicity and ICI sensitivity [33]. After establishing a genetic signature-based predictive biomarker for systemic therapy (pembrolizumab, anti-PD-1 ICI across many tumor types), the FDA awarded its first tissue-agnostic clearance for deficient mismatch repair (dMMR)/MSI-H malignancies [34]. The FDA approval of pembrolizumab in dMMR/MSI-H was based on the KEYNOTE-158 study. The study evaluated the efficacy of pembrolizumab in patients with advanced solid tumors that had progressed on standard therapy. They found that pembrolizumab showed promising results in patients with dMMR/MSI-H solid tumors, with an overall response rate of 34.3% and a median duration of response of 24.4 months. The study suggests that pembrolizumab may be an effective treatment option for patients with dMMR/MSI-H solid tumors, including some pancreatic cancers [35].
In research utilizing a newly produced highly metastatic clone of murine gastric cancer cells, YTN16P, it was shown that infusion of PD-1 mAb through the intravenous or intraperitoneal route lowered the rate of metastasis development on the mesenteric surface by 30–40% as a monotherapy [36]. Additionally, previous studies utilizing colon [37][38] or ovarian cancer cells [39][40][41] have shown that anti-PD-1 mAb may partially, but not fully, inhibit the development of PM in immunocompetent animals. Mouse models established using YTN16 and LmcMF are resistant to ICI treatment because CXCL12 derived from CAFs recruit M2 macrophages which secrete various cytokines, such as VEGF, IL-10, amphiregulin, and MMP-1 [42]. These cytokines exhaust CD8+ cells, either directly or indirectly. Furthermore, infiltration of CD8+ cells is inhibited due to the high intertumoral pressure associated with tumor fibrosis induced by CAFs. Although these models are resistant to ICI therapy, anti-CAF treatment recovered the therapeutic efficacy of the ICI [43].

4. Monoclonal Antibodies

4.1. MOC31PE Immunotoxin

The monoclonal antibody called MOC31PE is derived from the Pseudomonas exotoxin A (PE) and targets the epithelial cell adhesion molecule (EpCAM), a transmembrane glycoprotein that is significantly overexpressed in cancerous tissue, including HGSOC, and is expressed at small levels in normal tissue [44][45]. After attaching to the EpCAM-expressing surface of cancer cells, MOC31PE kills cells by deactivating crucial cellular functions. Additionally, MOC31PE has a competitive edge over earlier anti-EpCAM antibody-based treatments due to its “simpler” mode of action, requiring just binding to EpCAM-expressing cancer cells before directly promoting cancer cell death through toxin release inside the target cells [46][47]. The therapeutic efficacy of chemotherapy-resistant cancer cells can be enhanced by MOC31PE. Recently, it was shown that patients with metastatic carcinomas who express EpCAM showed good tolerance to systemic doses of MOC31PE [48].
The ImmunoPeCa experiment (NCT02219893), a phase 1 dose-escalation study carried out in 2017 [49], examined patients with peritoneal metastasis from colorectal cancer (CRC) after demonstrating anti-cancer efficacy in preclinical testing [46][50][51]. The MOC31PE immunotoxin was given intraperitoneally the day following surgery to 21 patients who had CRS/HIPEC for PC from CRC at four distinct dose levels. The medicine was found to be safe and well-tolerated, with no evidence of dose-limiting harm. Even though MOC31PE was not absorbed into the body very much, the levels in the peritoneal fluid were thought to be cytotoxic. Neutralizing antibodies were produced by all patients.

4.2. Catumaxomab

Catumaxomab is a rat-murine bispecific and trifunctional antibody that targets EpCAM and can have a long-lasting immunization effect [52][53]. In 2009, catumaxomab was approved in Europe as the first drug for malignant ascites linked to PC [54][55]. This bispecific monoclonal antibody can target immune systems and has a safe profile in clinical trials when administered intravenously (IP). Catumaxomab’s fragment-crystallizable (Fc) domain activates Fc-receptor types I, IIa, and III on NK cells, CD3+ T-cells, and EpCAM receptors, which are the substance’s two antigen-binding sites that it particularly targets. As a result of this mechanism, pro-apoptotic cytokines including IL-2, IL-12, and TNF phagocytose the targeted tumor cells, leading to cell death [56][57][58].
Many ovarian cancer patients may already have peritoneal metastases at the time of their diagnosis, and the presence of a significant amount of malignant ascites accelerates the disease’s development and distention. In a trial by Burges et al., catumaxomab was used to treat ascites in 23 ovarian cancer patients who had resistant to conventional treatment. Production of ascites was significantly reduced during catumaxomab therapy in response to increasing dosages. Twenty-eight days after the last infusion, only one of twenty-three patients who received treatment needed a paracentesis, which is still nearly 2 weeks longer than is usually necessary [59][60]. In a multicenter trial conducted by Wimberger et al., 258 patients with ovarian and non-gynecologic malignancies were randomly assigned to treatment and control groups to determine the effect of catumaxomab therapy on life quality. Patient surveys were used to determine the results. Compared to paracentesis alone, treatment with catumaxomab with paracentesis considerably delayed the period until the quality of life deteriorated [61]. The therapy of malignant ascites from EpCAM+ tumors was evaluated in a randomized, multicenter study by Heiss et al. Catumaxomab significantly enhanced median puncture-free survival and time to next therapeutic intervention in the experimental group, as well as overall survival, among 258 patients with gastric cancer in this phase II/III clinical trial [57].

5. Cancer Vaccines for Peritoneal Metastasis

Therapeutic vaccines against cancer are a further immunotherapy strategy that has attracted substantial recent advancements in the intraperitoneal developments of PC. Malignant ascites have a bad prognosis and are a significant barrier to the immune system responding to vaccines. To combat this, vaccines are currently being developed and modified to specifically target ascites to enhance the quality of life for PM patients. 

Cellular, viral vector, and molecular (peptide, DNA, or RNA) are the three main platforms for cancer vaccines [62]. Allogeneic tumor cell lines or autologous patient-derived tumor cells are used to create cellular vaccines [63]. Due to their functions as tumor antigen consumers, processors, and presenters, dendritic cells (DCs) are employed to create cellular cancer vaccines. Oncolytic viral vaccinations have been genetically altered to target and kill tumor cells [64]. In addition to their oncolytic effects, viral vectors also stimulate tumor-specific immune responses by providing tumor antigens through more typical T-cell priming procedures [65]. On the cell surface, major histocompatibility complex (MHC) peptides expression can be detected by T-cells [66]. For the creation of peptide-based cancer vaccines, it is important to know how peptides and T cell receptors interact with MHC. Enzymes break down short peptides, which are typically nine amino acid residues long, and immediately connect to MHC molecules, perhaps generating tolerance [67]. Longer peptides, typically 30 mer, are taken in by antigen-presenting cells (APCs), processed for MHC presentation, and result in memory CD4+ and CD8+ T cell immunological responses, which may make APCs more immunogenic [67]. DNA vaccines, often known as “naked DNA”, are closed circular DNA plasmids that encode TAAs and immunomodulatory substances intending to induce tumor-specific immune responses [68]. Despite being straightforward, secure, and quick to create, naked DNA vaccines are ineffective against target tumor cells due to low rates of transfection. mRNA vaccines, which are produced in vitro, encode an antigen or antigens, and following internalization, they express proteins that cause an immune reaction. mRNA vaccines may convey a large number of antigens and co-stimulatory signals without running the risk of infection or insertional mutagenesis, and their manufacture is rapid and affordable. However, the delivery effectiveness and stability are issues for mRNA vaccines [68].

Targeting ascites in PC has been accomplished by combining DCs with cytokine-induced killer cells (CIKs), which are cytotoxic T lymphocytes with a CD3+ CD56+ phenotype. The choice of CIKs was made based on three important criteria: they exhibit low cytotoxicity toward normal cells, no negative impact on hematopoiesis in the bone marrow, and resistance to Fas ligand-induced apoptosis. The effects of the combined treatment of DCs and CIKs include an increase in cytotoxic T cells in ascites that are driven by TNF and IFN and a reduction in immunosuppressive Tregs [69]. Similar to CAR-T cells, the method by which cancer vaccines are administered plays an important role in their dissemination. Natural killer cells (NKs) and dendritic cells (DCs) working together to fight tumors have been proven to be successful. Geller et al. demonstrated that IP- injection of IL-2-activated NK cells enhanced antitumor effects in an ovarian cancer mouse model xenograft, in contrast to systemic distribution [70].

Many cycles of patient-derived type I CD4+ T helper cells (Th1) provided by IP together with the cytokines IL-2 and IFN were shown to improve the anti-tumor activity of autologous CD8+ T cells against the tumor-specific glycoform of MUC1. This was reported by Dobrzanski et al. [71][72]. In a peritoneal metastatic colon cancer murine model, Alkayyal et al. further emphasized the relevance of combining pro-inflammatory cytokine IL-12 with an oncolytic virus (Maraba MG1) for reducing tumor burden in a CT26 colon cancer model. When MG1-IL12-ICV was IP-administered to these animals, it significantly decreased tumor development, created resistance to CT26 cell reinoculation, and improved survival. Regarding the mechanism, IL-12 was effective in enticing NK cells to the tumor location for annihilation. When paired with MG1 viral proteins, these activated NK cells generated IFN, which stimulated DCs and aided in the attraction of more NK cells [73]. 

6. CAR-T Cell Therapy for Peritoneal Carcinomatosis

6.1. Basic of CAR-T Cells

CAR-T cells have undergone genetic alteration to express chimeric receptors that allow them to target certain surface antigens regardless of a person’s major histocompatibility class. Although Gross et al. initially described this type of modified T cell in 1989, this technology has only evolved dramatically in the last decade, particularly for the treatment of hematologic malignancies [74]. Immunotherapy has grown in popularity since the development of CAR-T cells, which allow T cells to produce synthetic receptors against specific surface antigens and destroy tumor cells [75]. These antigens may bind to carbohydrates, glycolipids, proteoglycans, and proteins [76][77]. As a result of CAR-T cells’ therapeutic success in clinical trials of hematologic malignancies, more research is being conducted on its application to the treatment of therapy-resistant stage IV solid tumors. CAR-T cells are composed of extracellular single-chain variable fragments (scFv) of antibodies specific to the target tumor antigen and the T-cell activation domain. CAR-Ts, in contrast to specialized T-cell therapy, are MHC-independent due to the scFv component [78][79].

6.2. Administration Route of CAR-T for Peritoneal Carcinomas

Katz et al. provided the initial description of CAR-T therapy for PC, using CEA-targeting CAR-T cells to treat colorectal PC in an animal model. The authors noticed that intraperitoneal dispersion was superior to systemic injection. Compared to systemic therapy, intraperitoneal injection resulted in a higher tumor decrease and a longer-lasting impact. These data suggest that protection against recurrence and other distant metastases may be possible [80].
Ang et al. evaluated a mouse model of PC by employing mRNA transfection to generate CAR-T cells against EpCAM. This type of transfection had temporary effects, boosting safety in the case of adverse consequences. Due to the transient nature of the effect, repeated infusions are necessary for optimal outcomes [81]. These data suggest that local injection boosts CAR-T cell infiltration and trafficking, increases anticancer activity, increases recurrence protection, and enhances extraperitoneal antitumor efficacy while limiting systemic adverse effects. Solid tumors and PC still pose specific obstacles that must be solved. The microenvironment of the tumor, which generates an immunological and physical barrier, is the greatest impediment. The stroma of the tumor, which is rich in collagen in the extracellular matrix, is one of the components of the physical barrier. Due to the stroma, the tumor cells cannot be treated locally or systemically. However, collagenase can degrade this collagen, facilitating medication penetration [82].

6.3. CAR-T Cell Studies for Peritoneal Carcinomatosis

The transfer of T lymphocytes with the CAR (chimeric antigen receptor) gene, which is selective for tumor-associated antigens, across regional boundaries (TAAs) to the peritoneal cavity enhances the transfer of CAR-T cells to the disease location while decreasing or eliminating neurotoxicity and cytokine release syndrome.
CAR-T cells were examined as a potential new treatment option for ovarian cancer, which is often diagnosed in a late stage. Koneru et al. focused on the expanded extracellular domain MUC16 (MUC-16ecto) when treating advanced-stage ovarian cancer. To ensure that these CAR-Ts would activate and proliferate at the location of the tumor in the presence of immunological checkpoints, researchers engineered anti-MUC-16ecto CAR-T cells that produced IL-12. In a SCID Beige ovarian cancer xenograft model, these CAR-Ts had more efficacy than anti-MUC-16ecto CAR-T cells without an IL-12 arm to enhance antitumor activity and mouse survival when delivered intraperitoneally (IP) [83].

This entry is adapted from the peer-reviewed paper 10.3390/cancers15082383

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