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Scientists push CAR T cell therapy beyond blood cancers, unlocking potential for targeting solid tumors with enhanced delivery, resilience, and precision in the face of tough obstacles. Study: Beyond the blood: expanding CAR T cell therapy to solid tumors . Image Credit: Nemes Laszlo / Shutterstock In a recent study published in the journal Nature Biotechnology , a group of authors explored recent advances in Chimeric antigen receptor (CAR) T cell therapy for solid tumors, analyzing key challenges and strategies to enhance therapeutic outcomes.
Background CAR T cell therapy has revolutionized cancer treatment, achieving significant success in hematological cancers through targeted immunotherapy . However, translating this success to solid tumors has proven challenging due to unique obstacles such as the hostile tumor microenvironment, which induces CAR T cell dysfunction, and tumor heterogeneity, which complicates effective targeting. Additionally, the physical barriers within solid tumors impede CAR T cell infiltration, reducing therapeutic efficacy .
While recent clinical trials show promise in treating specific solid tumors, further research is needed to develop innovative approaches to overcome these challenges and enhance the potential of CAR T cell therapy . Challenges in treating solid tumors Tumor microenvironment (TME) barriers Solid tumors create a hostile microenvironment with immunosuppressive factors, such as regulatory T cells and tumor-associated macrophages, leading to CAR T cell exhaustion. Low pH, hypoxia (Low oxygen in tissues), and nutrient scarcity further degrade CAR T cell effectiveness, making sustained responses challenging.
Limited trafficking and persistence Physical and biochemical barriers in solid tumors hinder CAR T cells from reaching and persisting at the tumor site, diminishing their efficacy over time. Tumor heterogeneity Solid tumors consist of diverse cancer cell subpopulations with varied or lost antigens, complicating effective CAR T cell targeting and allowing immune escape. Recent advances in CAR T cell therapy for solid tumors Innovations in CAR engineering Advancements in CAR T cell engineering have focused on enhancing cell resilience and functionality within solid tumor environments.
For example, "armored" CAR T cells are being developed to secrete cytokines that counteract immunosuppressive signals within the TME, potentially improving their survival and activity. Bispecific and trispecific CARs, which can recognize multiple antigens, have also been explored to address tumor heterogeneity and improve targeting accuracy. Additionally, CARs with synthetic biology components, such as AND/OR logic gates, allow CAR T cells to respond more precisely to complex antigen patterns in solid tumors.
Locoregional delivery methods To improve CAR T cell trafficking and effectiveness, locoregional delivery techniques are being investigated. These methods involve directly injecting CAR T cells into or near tumor sites, bypassing many of the barriers present in the systemic circulation. Clinical trials have shown promising results for locoregional CAR T cell delivery in brain tumors and pleural malignancies.
This targeted approach can enhance cell concentration at the tumor site, increase efficacy, and reduce potential systemic side effects. Combination therapies with CAR T cells Combining CAR T cell therapy with other treatments, such as immune checkpoint inhibitors, lymphodepletion chemotherapy, or radiotherapy, can potentially enhance CAR T cell activity and persistence. Lymphodepleting chemotherapy can help modulate the TME to be less immunosuppressive, supporting CAR T cell expansion and activity.
Radiotherapy, in particular, can remodel the TME and make it more conducive to CAR T cell infiltration. Immunotherapy agents like checkpoint inhibitors have also been combined with CAR T cells to reduce immune suppression and reinvigorate T cell responses within tumors. Promising clinical results in solid tumors Recent clinical trials have reported promising outcomes for CAR T cell therapy in certain solid tumor types, such as neuroblastoma (a childhood nerve cell cancer, often in adrenal glands), glioblastoma (an aggressive brain cancer from glial cells ), and gastrointestinal cancers.
Similarly, trials involving CAR T cells targeting Human Epidermal Growth Factor Receptor 2 (HER2), Epidermal Growth Factor Receptor (EGFR), and Claudin18.2 in sarcoma and gastrointestinal tumors have demonstrated encouraging response rates despite the challenges. These results suggest that CAR T cell therapy, with further refinement, could become a viable option for solid tumors.
Future Directions Targeting tumor heterogeneity To address tumor heterogeneity, next-generation CAR T cells are being developed with multiple targeting capabilities, such as bispecific CARs or mixed CAR T cell populations, to recognize different tumor antigens simultaneously. This multi-targeting approach aims to reduce the risk of immune escape by covering a broader range of tumor antigens, thus enhancing efficacy. Enhancing CAR T cell metabolic resilience Another research focus is on engineering CAR T cells to be more resilient to the metabolic challenges posed by the TME.
Strategies such as hypoxia-responsive CARs, which are only activated in low-oxygen environments, and the incorporation of metabolic support mechanisms can help CAR T cells thrive within solid tumors. Efforts to reprogram T cell metabolism using pharmacologic agents are also underway to improve CAR T cell persistence and activity. Safety enhancements and synthetic biology tools Ensuring the safety of CAR T cell therapy, especially with multi-targeted and cytokine-secreting CARs, is a priority.
Switchable CARs and inducible suicide genes offer options to control CAR T cell activity in case of severe adverse reactions. Additionally, synthetic biology tools like universal CARs, which can be adapted to target various antigens, offer flexibility and safety, potentially enabling more tailored and controllable therapies for solid tumors. Conclusions To summarize, CAR T cell therapy holds promise for treating solid tumors despite challenges such as limited cell trafficking, tumor heterogeneity, and an immunosuppressive microenvironment.
Recent advancements in CAR engineering, including bispecific CARs, locoregional delivery, and combination therapies, have shown encouraging results in clinical trials, indicating the potential for broader applications beyond blood cancers. Uslu, U., June, C.
H. Beyond the blood: expanding CAR T cell therapy to solid tumors. Nat Biotechnol (2024), DOI - 10.
1038/s41587-024-02446-2, https://www.nature.com/articles/s41587-024-02446-2.
