Navigating Cancer Treatment Options

T cell immunotherapy has had success in treating haematogenous cancers over the years, but it has struggled to treat solid tumour cancers. Looking at the literature available for gamma-delta T cells, there does not appear to be much reported progress on use of gamma-delta cells to treat gastric cancer. Two prominent papers appear to show effect in 7 patients, but this pilot study was performed in 2014 with no apparent follow up easily searchable. A second study in 2017 looks at in vitro effects of gamma delta T cells on tumour tissue.

In comparison, CART T cells have far more literature and research available, showing greater jumps in targeting various expressed antigens, and also with recent clinical trials rather than in-vitro experiments. Of course, all of the data is still experimental, but with a cursory look, CART appears to be the more eligible candidate.

Tumor-Activated TCR? ? + T Cells from Gastric Cancer Patients Induce the Antitumor Immune Response of TCR? ? + T Cells via Their Antigen-Presenting Cell-Like Effects 2014

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988731/

We conducted a pilot study to evaluate the safety of weekly intraperitoneal injections of in vitro expanded V?9V?2 T cells together with zoledronate for the treatment of such malignant ascites. Patient peripheral blood mononuclear cells were stimulated with zoledronate (5 ?mol/L) and interleukin?2 (1000 IU/mL). After 14 days culture, V?9V?2 T?cells were harvested and administered intraperitoneally in four weekly infusions.

The number of tumor cells in the ascites was significantly reduced even after the first round of therapy and remained substantially lower over the course of treatment. IFN?? was detected in the ascites on treatment. Computed tomography revealed a significant reduction in volume of ascites in two of seven patients. Thus, injection of these antitumor V?9V?2 T?cells can result in local control of malignant ascites in patients for whom no standard therapy apart from paracentesis is available.

Tumor-infiltrating ??T cells predict prognosis and adjuvant chemotherapeutic benefit in patients with gastric cancer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674957/ gastric cancer

2017

The present study shows that intense ??T cells infiltration is an independent prognostic factor in patients with gastric cancer and is predictive of a survival benefit from adjuvant chemotherapy in patients with TNM II and III disease. – IN VITRO STUDY

CART

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355670/ CAR-T Cell Therapy

CAR-T Cell Therapy—An Overview of Targets in Gastric Cancer

Gastric cancer (GC) is one of the most commonly diagnosed malignancies and, unfortunately, still has a high mortality rate. Recent research points to CAR-T immunotherapy as a promising treatment for this disease. Using genetically engineered T cells designed to target a previously selected antigen, researchers are able to harness the natural anti-tumor activity of T cells. For therapy to be successful, however, it is essential to choose antigens that are present on tumor cells but not on healthy cells. In this review, we present an overview of the most important targets for CAR-T therapy in the context of GC, including their biologic function and therapeutic application. A number of clinical studies point to the following as important markers in GC: human epidermal growth factor receptor 2, carcinoembryonic antigen, mucin 1, epithelial cell adhesion molecule, claudin 18.2, mesothelin, natural-killer receptor group 2 member D, and folate receptor 1. Although these markers have been met with some success, the search for new and improved targets continues. Key among these novel biomarkers are the B7H6 ligand, actin-related protein 2/3 (ARP 2/3), neuropilin-1 (NRP-1), desmocollin 2 (DSC2), anion exchanger 1 (AF1), and cancer-related antigens CA-72-4 and CA-19-9.

HER-2

HER2 is a surface antigen from the epidermal growth factor receptor

In GC, HER2 is overexpressed in 10–20% of diagnosed cases. It is presumed that HER2 overexpression is already present in the early stages of carcinogenesis [19], and this supports GC stem cells [18].

Trastuzumab is a commonly used therapeutic agent for HER2-positive gastric tumors, which is often used in combination with chemotherapy. About one year after starting trastuzumab treatment, resistance mechanisms that cause treatment failure appear.

Studies have shown that the use of HER2 in CAR-T cell therapy is an effective method to treat GC, and its use reduces the need for combined therapies, as is the case with trastuzumab. HER2-directed CAR-T cells have high affinity for GC cells, even for cells with low HER2 expression. In addition, CART-HER2 cells may be an effective agent in preventing disease remission and metastasis initiation

CEA

CEA is a glycoprotein expressed on the epithelial cells of the gastrointestinal tract and lungs.

A high level of CEA is associated with a poor prognosis and signals the possibility of metastases [25].

Research into CEA-specific CAR-T cell therapies has shown that the use of CART-CEA cells contributes to the prolongation of survival time in mice with advanced GC and the slowing down of tumor growth [4].

In addition, CEA-targeted therapy has been found to promote T cell accumulation in the tumor environment [12] without destroying healthy cells and, therefore, it constitutes an excellent therapeutic target [26]. Moreover, recent reports show that the effectiveness of CART-CEA therapy can be improved by the use of cytokines. In particular, recombinant human interleukin (IL)-12 has been shown to increase the anti-cancer activity of CAR-T cells. Therefore, a strategy using cytokines to enhance the therapeutic effect of CART-CEA should be developed [27].

2.3. MUC1

In September 2019, Minerva Biotechnologies opened a clinical trial to assess the use of CAR-T cells targeting MUC1* in metastatic breast cancer. Although MUC1 is expressed in solid tumors, it is cleaved and shed from the cell surface as the tumor stage progresses, which limits the effectiveness of anti-MUC1 CAR-T cells. MUC1* is an antigen that is revealed when MUC1 is cleaved. This CAR-T cell therapy uses the MNC2 antibody, which recognizes an epitope on MUC1* that is revealed when MUC1 is cleaved on tumor cells but not on healthy cells. Results of in vitro and in vivo experiments have shown CART-MUC1 cells targeting and killing breast cancer tumor cells. If tests in humans are successful, this could be a promising therapy for other solid tumors, such as GC [36].

2.4. EpCAM

EpCAM is a transmembrane glycoprotein also known as CD326. It is expressed in epithelial tissues, on the basolateral cell surface [37]. EpCAM plays an important role in cell signalling, differentiation, migration, and proliferation and, therefore, plays a key role in tumorigenesis and metastasis [38,39,40,41].

EpCAM is an excellent target for various therapeutic methods, including immunotherapy, because it is expressed uniformly on the whole surface of neoplastic cells [41,42]. The overexpression of EpCAM is associated with a poor prognosis in patients with multiple tumors, and its level can be used as a marker for circulating neoplastic cells (CTC) involved in metastasis [42].

EpCAM is overexpressed in >90% of gastric tumors, and consequently, its use as a therapeutic target is encouraging [38,43]. CAR-T cells directed against EpCAM were shown to be safe and effective in the treatment of solid tumors overexpressing this glycoprotein [44]. Clinical trials evaluating this therapy in the treatment of GC were completed in 2019 [43].

CLDN 18.2

CLDN 18.2 is the second isoform of claudine 18, located on the outer cell membrane. Under normal conditions, it is expressed in differentiated epithelial cells of the gastric mucosa, but it is also present in primary GCs [45,46]. CLDN 18.2 is expressed in 70% of primary gastric adenocarcinomas and their metastases [47], and CLDN18.2 activation is also present in pancreatic, oesophageal, ovarian, and pulmonary tumours. Thus, it is considered a potential candidate for targeted GC therapy [45,46].

Detailed studies using CAR-T cell therapy against CLDN 18.2 are ongoing as its use in the treatment of GC, as well as other CLDN 18.2-positive tumours, is promising [48]. Clinical trials to evaluate the efficacy and safety of this method in the treatment of GC in humans will end in 2021 [49].

The FDA has recently granted clearance for the use of CT041, anti-CLDN18.2 CART cells, in patients with CLDN18.2-expressing stomach, pancreatic, and gastroesophageal junction adenocarcinoma [50]. Results from a phase I clinical trial published in 2019 show a total objective response rate of 33% in a small group of patients with advanced gastric or pancreatic cancers, with no serious side effects [49]. An open label, multicentre, Phase 1b clinical trial is planned for September 2020 in the USA to evaluate the safety and efficacy of this therapy in patients with advanced gastric or pancreatic adenocarcinoma [51].