Hyderabad: Breaking down a tumour’s physical and immune defences before deploying engineered immune cells could improve treatment of hard-to-penetrate solid cancers such as pancreatic ductal adenocarcinoma and glioblastoma, according to a review led by researchers at the CSIR-Centre for Cellular and Molecular Biology (CCMB).The paper, ‘Integrated systems from small molecule modulators to next generation cell engineering: the emerging frontier in immuno-oncology’, proposes combining small-molecule drugs, checkpoint inhibitors and engineered cell therapies rather than relying on a single treatment. It has been published as an article in Cell Communication and Signaling journal.Opening up tumour barriersUnlike chemotherapy, which broadly targets rapidly dividing cells, immunotherapy activates the body’s immune system to recognise and attack cancer cells. However, tumours can evade immune surveillance by reducing MHC-I antigen presentation, releasing immunosuppressive cytokines and increasing the expression of immune checkpoint proteins.According to the review, small-molecule compounds can penetrate tumour tissue and target intracellular signalling and metabolic processes. They could help weaken the fibrotic stroma and suppress regulatory T cells and myeloid-derived suppressor cells.One proposed strategy is to use agents such as the FAK inhibitor defactinib or oncolytic viruses to make immunologically inactive, or “cold” tumours more receptive to subsequent treatment with checkpoint inhibitors or adoptive cell therapies.Focus on engineered immune cellsThe researchers examined monoclonal antibodies, cancer vaccines, checkpoint inhibitors and adoptive cell therapies such as tumour-infiltrating lymphocytes (TILs), TCR-T, CAR-T and CAR-NK cells.While CAR-T therapy has demonstrated significant efficacy in some blood cancers, its application to solid tumours remains challenging because of physical barriers, an immunosuppressive tumour microenvironment and antigen escape.CAR-NK cells could offer an allogeneic, “off-the-shelf” approach, with MHC-independent cancer-cell killing and a potentially lower risk of cytokine release syndrome. The review also highlights hydrogels, nanoparticles, and scaffolds as potential technologies to improve the delivery, persistence, and activity of engineered immune cells within tumours.The authors are Mridul Gautam, Chethana D Kumar, Charan Raju Tangella, Pournami Ramachandran, Marco Cordani and corresponding author Lekha Dinesh Kumar. The researchers are affiliated with CCMB, University Hospital Coventry and Complutense University of Madrid.The review argues that future combination therapies should be guided by biomarkers, multi-omic profiling and patient-specific factors, including age, immunosenescence, comorbidities and sex-linked differences in pharmacokinetics.It also identifies CAR-NK cells and mRNA–lipid nanoparticle platforms as promising approaches that could potentially reduce manufacturing time and improve the accessibility of engineered cell therapies.
