Published in the journal Trends in Biotechnology, the strategy addresses the lack of surface antigens that typically renders chondrosarcoma unresponsive to standard immunotherapies like CAR-T cells and cancer vaccines.
Targeting Chondrosarcoma Limitations
Chondrosarcoma is the second most frequent malignant bone tumor, characterized by high malignancy, frequent lung metastasis, and poor prognosis. Because traditional chemotherapy and radiation yield low response rates, surgical resection remains the primary treatment. For patients with unresectable or metastatic tumors, the 10-year survival rate drops below 30 percent.
Standard immunotherapies struggle against chondrosarcoma because the tumor cells lack surface antigen targets that allow immune cells to identify and attack them. Clinical trials utilizing immune checkpoint inhibitors have failed to demonstrate clear therapeutic efficacy for this reason. The joint research team bypassed the need to find naturally occurring antigens by engineering cancer cells to build their own targets, moving away from searching for antigens naturally present in cancer cells and toward an approach where cancer cells directly generate targets so they can be recognized by immune cells.
Designing the Genetic Circuit
The research team analyzed DNA switch promoters to identify EGR1 and KLF13 promoters that selectively activate within chondrosarcoma. They designed an AND-gate genetic circuit requiring both promoters to activate simultaneously. This circuit triggers the production of a T-cell engager—a synthetic protein that binds T-cells closely to the cancer cells to stimulate an immune attack.
Laboratory experiments showed that the design restricts the treatment protein’s expression to chondrosarcoma cells while sparing normal tissue, implementing a gene therapy strategy that selectively forms immune targets in chondrosarcoma cells while suppressing therapeutic protein expression in normal tissues. To counter the cancer’s defense mechanisms, the team identified MIF as a core factor suppressing T-cell responses. Patient tissue analysis revealed that higher MIF expression correlates with increased malignancy and lower survival rates.
Dual Approach Reduces Tumor Size in Mice
Testing the dual approach on mice transplanted with human immune cells and dual-sided tumors yielded significant results. Administering the genetic circuit alongside a MIF-blocking antibody reduced tumor size. Treating only one side's tumor triggered an abscopal effect, shrinking the untreated tumor on the opposite side as a local immune response affected tumors at other sites.
While the findings establish a potential therapeutic strategy for chondrosarcoma and other antigen-poor cancers, the team emphasized that the results are currently limited to experimental models and expects this combination immunotherapy strategy could potentially apply not only to systemic treatment of chondrosarcoma but also to other cancer types lacking immune target antigens. Verifying safety and efficacy in human patients requires additional preclinical studies and clinical trials.
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