Editorial: Immunotherapy Resistance and Advancing Adaptive Cell Therapeutics

Luciana Rodrigues Carvalho Barros^1*Amar Yeware²

• ¹Institute of Cancer of São Paulo, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
• ²University of Wisconsin-Madison, Madison, United States

and naive natural killer (NK) and T cells or other kinds, including mesenchymal stem cells (MSC). Although cord blood needs an in vitro purification and expansion, it effectively has a lower level of checkpoint inhibitors, such as PD1, LAG3, and TIM3 expression, than allogeneic PB-derived CAR cells.Beyond the type of cell source, T cells and NK cells are the main effector cells carrying CAR for cancer therapy. A main concern with CAR-T or CAR-NK cells is their capacity to migrate and persist in the tumor. All immune cells migrate via chemokine gradient into the tumor microenvironment. In the case of myeloma, bone marrow is the main site, and a chemokine CXCL12 may attract NK and T cells, increasing the chance of therapy success. For solid tumors, ACT is challenging due to low cell migration, inhibitory microenvironment, and especially antigen expression heterogeneity within the tumor. CAR-T cell, NK, dendritic cell-based vaccines, and tumor-infiltrating lymphocytes (TIL) are the main strategies presented to treat solid tumors. Several studies were reviewed by Ao et al for biliary tract malignancies, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer (4). These tumors are aggressive, with a poor prognosis of a few months of overall survival despite chemotherapy. These tumors are of low incidence in the West, but 40 times higher incidence in Asian countries. A combination of ACT may be tested in the future as an alternative to the current chemotherapy to improve the prognosis.In ACT, especially when expanding and re-injection of TILs or CAR-T, the functional quality of these cells could become critical. For example, the meta-analysis evaluated by Wan Z et al, indicated that high PD-1 expression on CD8+ cells based on 20 studies involving 3,086 patients, was linked to poorer overall survival (6). However, if the injected T cells have already acquired exhaustion phenotypes like PD-1 upregulation in the tumor microenvironment, their anti-tumor efficacy may be compromised. Furthermore, the case study suggested that the use of checkpoint inhibitors such as Pembrolizumab in combination with chemotherapy could lead to cytokine release syndrome or hemophagocytic lymphohistiocytosis (7). Therefore, it underscores the need for strategies that either select for non-exhausted adaptive T cells or genetically knockout T cells for checkpoints to enhance ACT outcome.Adaptive cells and CAR cell-based therapies are currently in clinical use for cancer, especially hematological, facing challenges in availability and cost to reach more patients.On the other hand, adaptive cell therapies for autoimmune diseases are in Phase 1 or 2 clinical trials. As revised by Fu et al, autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis can be managed by pharmacotherapy or ACT (5). In the latter, regulatory T (Treg) or CAR-Treg cells, chimeric auto-antibody receptor T cells, regulatory NK,and tolerogenic Dendritic cells can be used as ACT. Although none of these strategies are approved for autoimmune diseases, the future seems to be a combination of drugs and ACT.Diverse approaches are being investigated to enhance ACT and immunotherapeutics, including the use of machine learning to integrate multi-omics data for precise prognostic modeling. Yan H et al. identified an immunogenic cell death-related signature (ICDRS) using single-cell and bulk RNA sequencing data, offering valuable insights into tumor immune evasion in bladder cancer (6). This approach could make it possible to identify patient-specific features, enabling more personalized ACT or its combination with immunotherapeutic strategies.In conclusion, ACT and advanced immunotherapeutics hold immense potential for treating cancer or autoimmune diseases by developing and engineering immune cells in different ways alongside the CAR receptors. While current challenges of its resistance, cell exhaustion, and manufacturing hurdles persist, ongoing innovations and personalized approaches could pave the way for more effective and accessible therapies.