Understanding and improving cellular immunotherapies against cancer: From cell-manufacturing to tumor-immune models

The tumor microenvironment (TME) is shaped by dynamic metabolic and immune interactions between precancerous and cancerous tumor cells and stromal cells like epithelial cells, fibroblasts, endothelial cells, and hematopoietically-derived immune cells. The metabolic states of the TME, including the hypoxic and acidic niches, influence the immunosuppressive phenotypes of the stromal and immune cells, which confers resistance to both host-mediated tumor killing and therapeutics. Numerous in vitro TME platforms for studying immunotherapies, including cell therapies, are being developed. However, we do not yet understand which immune and stromal components are most critical and how much model complexity is needed to answer specific questions. In addition, scalable sourcing and quality-control of appropriate TME cells for reproducibly manufacturing these platforms remain challenging. In this regard, lessons from the manufacturing of immunomodulatory cell therapies could provide helpful guidance. Although immune cell therapies have shown unprecedented results in hematological cancers and hold promise in solid tumors, their manufacture poses significant scale, cost, and quality control challenges. This review first provides an overview of the in vivo TME, discussing the most influential cell populations in the tumor-immune landscape. Next, we summarize current approaches for cell therapies against cancers and the relevant manufacturing platforms. We then evaluate current immune-tumor models of the TME and immunotherapies, highlighting the complexity, architecture, function, and cell sources. Finally, we present the technical and fundamental knowledge gaps in both cell manufacturing systems and immune-TME models that must be addressed to elucidate the interactions between endogenous tumor immunity and exogenous engineered immunity.