To date, oncologists have not seen much success with immunotherapy for neuroendocrine tumors (NETs). Xianxin Hua, MD, PhD, and a team at the University of Pennsylvania may be on the verge of changing that disappointing history.

Hua, a professor of cancer biology with Abramson Family Cancer Research Institute, leads a team that has developed CAR T cells targeting CDH17, a cell surface adhesion protein that is frequently upregulated in NETs and gastrointestinal tumors. These anti-CDH17 CAR T cells successfully eradicated NET tumor cells in mice and in human cells 

 The CAR T cells also suppressed gastric, pancreatic, and colorectal cancers in tumor xenografts or autochthonous primary mouse models. Moreover, this therapy targeted tumor cells while sparing healthy tissue.

“Initially, to our dismay, we found that these CDH17 cells are also expressed in normal epithelial cells,” Hua said in an interview with 

. Typically, he said, investigators would detect CDH17, use that to target the tumor, and kill the tumor.

“However, because CDH17 is expressing in the epithelia, you're going to kill the epithelial cell. Then you’re going to have a very damaging effect for the normal issue. That’s a nonstarter,” Hua said. “Surprisingly, our data convincingly demonstrates that the CAR T cells specifically attack the tumor cells.”

Hua added that normal epithelial cells form a very tight bond with their neighboring cells that does not allow water or nutrients in the intestine to pass between them. CDH17 creates a seal between those cells, masking them from the attacking CAR T cells. In contrast, as noted by Hua and colleagues noted in findings recently published in 

, “NET cells lost polarity of CDH17 distribution, allowing CDH17 displayed all over the tumor cell surface, attracting potent CAR T attack.”

In their models, investigators found that 85.7% of well-differentiated NETs collected in the small bowel were positive for CDH17 expression compared with 40-50% of pancreatic NETs, suggesting that this modality could be particularly effective in targeting NETs in the intestines.

Penn has licensed this CAR T cell technology Chimeric Therapeutics. Hua hopes in-human trials will begin in late 2022 or early 2023.

There are more than 12,000 new diagnoses of NETs in the United States annually with 175,000 people living with the disease, according to the American Society of Clinical Oncology (ASCO).

 NETs can appear in the lung, small intestine, rectum, colon, pancreas, or stomach.

Patients with rectal NETs have the best 5-year OS at 55.7% compared with just 22.7% for patients with pancreatic NETs. According to an analysis of the Surveillance Epidemiology and Ends Results database taken from 1973 to 2014, the 5-year OS for all NETs was 39.4%.

NETs are difficult to diagnose, and symptoms vary widely depending on site of disease. Hua said that in other colorectal cancers such as gastric cancer, tumors are easy to spot on endoscopy because they develop on the surface of the intestinal epithelia. NETs, on the other hand, develop very close to the outer side of the intestine or to the plasma membrane.

“Therefore, it’s very difficult to diagnose and even at a surgery,” he said. “Some surgeons have challenges or seeing a clear boundary—sometimes they have to feel with a finger.”

The incidence of gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs) has grown steadily in Asia, Europe, and particularly North America. In the United States, diagnoses have grown from 1.5 cases per 1,000,000 in 1973 to 4.6 cases per 1,000,000 in 2012.

 Although imaging and detection have improved during that time, investigators said that does not account for all of the growth.

Albertelli et al called the evidence supporting immunotherapy in NETs “disappointing” in a 2021 paper.

 However, investigators have realized a handful of successes with immunotherapeutic agents. The FDA approved the PD-1 inhibitor atezolizumab (Tecentriq) plus carboplatin and etoposide for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) in March 2019 based on findings from the phase IMpower133 (NCT02763579) trial.

In IMpower133, 403 patients with ES-SCLC who received no prior chemotherapy for extensive stage disease and had ECOG performance status 0 or 1 were assigned to atezolizumab plus carboplatin and etoposide or placebo plus carboplatin.

The median overall survival (OS) was 12.3 months (range, 10.8-15.9) in the atezolizumab group vs 10.3 months (range, 9.3-11.3) in the control group (HR, 0.70; 95% CI, 0.54, 0.91; 

 = .0069). The median progression-free survival (PFS) also favored the experimental arm (5.2 vs 4.3 months; HR 0.77; 95% CI, 0.62,-0.96; 

In updated results published in 2021, the median OS was 12.3 in the atezolizumab arm vs 10.3 months for the control arm (HR, 0.76; 95% CI, 0.60-0.95; 

“This development was very significant. To my knowledge, this was the first combination treatment approved by the FDA for lung NETs in more than 20 years,” Hua said. “However, as you can see, the mean OS only increased by a couple of months, illustrating the graveness of this disease and demonstrating that there is room to improve.”

In 2021, a team of international investigators published phase 2 (NCT02955069)

data evaluating the humanized IgG4 anti-PD-1 antibody spartalizumab (PDR001) in adults with advanced or metastatic, well-differentiated grade 1 or 2 non-functional gastrointestinal, pancreatic, or lung NETs (n = 95) or metastatic poorly differentiated GEP-NETs (n = 21). Patients received 400 mg spartalizumab every 4 weeks until progression or unacceptable toxicity.

The overall response rate (ORR) was 7.4% in the well-differentiated group, failing to meet the primary endpoint. However, investigators found that ORR was 16.5% (95% CI, 5.6%-34.7%) in patients with lung NETs (n = 5), warranting further evaluation.

In contrast to immunotherapy, oncologists have had more success treating NETs with targeted therapies. In 2018, the FDA approved lutetium Lu 

for patients with somatostatin receptor-positive GEP-NETs based on results of the phase 3 NETTER-1 trial (NCT01578239).

Updated results presented at the 2021 World Congress on Gastrointestinal Cancer showed that, compared with high-dose octreotide,

Lu-Dotatate significantly improved median OS (48.0 vs 36.3 months) in patients progressive midgut NETs. Including patients who crossed over from the control arm, the radioligand reduced the risk for death by 27% (HR, 0.73; 95% CI, 0.40-1.34).

Feng Z, He X, Zhang X, et al. Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues. 

. Published online March 21, 2022. doi: 10.1038/s43018-022-00344-7

Das S, Dasari A. Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: are there global differences? 

. 2021;23(4):43. doi:10.1007/s11912-021-01029-7

Albertelli M, Dotto A, Nista F, et al. Present and future of immunotherapy in neuroendocrine tumors. 

. 2021;22:615-636. doi: 10.1007/s11154-021-09647-z

FDA approves atezolizumab for extensive-stage small cell lung cancer. News release. March 19, 2019. Accessed May 23, 2022. 

Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. 

. 2018;379(23):2220-2229. doi: 10.1056/NEJMoa1809064

Liu SV, Reck M, Mansfield AS, et al. updated overall survival and pd-l1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). 

. 2021;39(6):619-630. doi: 10.1200/JCO.20.01055

Yao JC, Strosberg J, Fazio N, et al. Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neoplasms. 

. 2021:ERC-20-0382.R1. doi: 10.1530/ERC-20-0382

Cancer.org. Neuroendocrine tumors: statistics. February 2022. Accessed May 23, 2022. 

Man D, Wu J, Shen Z, Zhu X. Prognosis of patients with neuroendocrine tumor: a SEER database analysis. 

. 2018;10:5629-5638. doi: 10.2147/CMAR.S174907

Strosberg JR, Caplin ME, Kunz PL,et al. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. 

. 2021;22(12):1752-1763. doi: 10.1016/S1470-2045(21)00572-6

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To date, oncologists have not seen much success with immunotherapy for neuroendocrine tumors.

Xianxin Hua, MD, PhD

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