China dominates in vivo CAR-T trials while a pancreatic cancer study shows how the liver feeds metastases with serine

The external story reports that China has become a hotspot for developing and trialling in vivo CAR-T cell therapies: of the 140 in vivo CAR-T-cell drugs being tested in animals and people globally, 82% are being developed by groups in China, while most foundational, preclinical work has been done by groups in the United States and Germany. The story attributes this to China's large population, fast-track regulatory pathways and resources, and quotes researchers saying the investigator-initiated trial (IIT) pathway, which allows rapid testing in people without supervision from the drug regulator, is probably the main driving force behind China's growth in cell and gene therapies. The basis is an analysis published last month by John Wu at Boston Consulting Group and colleagues, plus comments from Emily Blyth at The Westmead Institute for Medical Research and Xiaoyuan Chen at Shandong Cancer Hospital and Institute; the story also cites early human results: the first in-human trial of in vivo CAR-T for an autoimmune disease reported that five people with treatment-resistant lupus showed improved symptoms three months after treatment with no serious side effects, and this month researchers in China reported improved symptoms in 16 people with autoimmune diseases.

A Nature study in the same bundle proposes and tests a tumour–hepatocyte metabolic cross-talk axis: PHGDH-deficient, exogenous-serine (exSer)-dependent pancreatic ductal adenocarcinoma (PDAC) cells activate PI3K–AKT signalling in hepatocytes through CXCL5–CXCR2, sequestering FOXO3A in the cytoplasm and derepressing PHGDH transcription, thereby enhancing serine production in hepatocytes. It was previously known that exSer-dependent PDAC cells at the primary site rely on neuron–tumour metabolic cross-talk for serine, but how they adapt to the metastatic liver niche was unclear; the study shows serine acquisition is organ-dependent, with liver metastases showing no clear increase in innervation and instead engaging a CXCL5-associated, hepatocyte-dependent supply program. The study found that 10 of 32 human PDAC liver-metastasis samples (31.3%) were PHGDH-negative in tumour cells, with strong PHGDH expression in adjacent hepatocytes; in mice it combined hepatocyte-specific Phgdh or Cxcr2 deletion, Cxcl5 knockout, 13C6-glucose tracing, ChIP–qPCR and a non-phosphorylatable FOXO3A(AAA) mutant.

The study shows that blocking this axis reduces liver metastatic burden and prolongs survival: under a serine- and glycine-deficient (−SG) diet, hepatocyte-specific deletion of Phgdh or Cxcr2, or deletion of Cxcl5 in tumour cells, markedly reduced the liver-metastasis burden of exSer-dependent PDAC, and the CXCR2 inhibitor SB225002 combined with a −SG diet reduced metastatic area and prolonged survival in tumour-bearing mice. The study further validated this in a spontaneous metastasis model: after orthotopic implantation and primary tumour resection at three weeks, CXCR2 inhibition given either 2 days or 2 weeks after implantation reduced liver metastasis of sgPhgdh cells but had no effect on primary tumour growth, indicating the strategy is directed at the liver metastatic niche rather than the primary tumour. Conclusions rest on multiple mouse experiments (whole liver weight and MetFinder-quantified tumour area, survival curves, and a post-resection recurrence model), and the study notes that the CXCR1/2 inhibitor SX-682 has entered clinical testing for PDAC (NCT04477343) and that the safety and feasibility of a −SG diet have been demonstrated in a phase I trial.

The study provides preclinical rationale for a liver-metastasis-directed strategy in the PHGDH-deficient, exSer-dependent PDAC subtype, suited to peri-operative or post-resection settings where suppressing liver metastatic recurrence is the goal, and it suggests PHGDH immunostaining of resected specimens or pre-operative EUS-FNA biopsies could help identify patients most likely to benefit. At the news level, the picture is relevant to researchers, companies and policymakers tracking cell and gene therapy development, regulatory pathways and international collaboration, since interest from international groups in collaborating with China on these therapies is growing.

The study's authors note that the human analyses used rapid-autopsy specimens reflecting end-stage disease, so tumour serine demand and hepatocyte serine supply might be accentuated by reduced food intake and cachexia-associated declines in circulating serine; the liver metastatic niche during early colonization warrants separate investigation, as does the conservation of PHGDH status between matched primary tumours and liver metastases. The mechanisms driving CXCL5 induction in PDAC cells and serine efflux from hepatocytes remain unresolved, and the extent to which hepatocyte-derived serine supports tumour growth in human disease, and whether this dependency is even greater under standard dietary conditions, remains unclear; if the latter is the case, dietary serine restriction could prove dispensable in patients. In addition, CXCR2 inhibition is not hepatocyte-specific, so the anti-metastatic effects cannot be attributed solely to blockade of hepatocyte CXCR2, and whether it offers an advantage over systemic PHGDH inhibition remains unresolved. On the news side, the early human in vivo CAR-T data come from limited samples, and developers will need to produce data showing long-lasting benefits and overcome toxic side effects reported with ex vivo CAR-T before regulatory approvals for widespread use.