After years of development, chimeric antigen receptor (CAR) T cell therapy has become a revolutionary method for cancer treatment. Among them, CD19 targeting drugs have achieved unprecedented success in the treatment of B-cell malignancies and were approved by the US FDA in 2017. In the previous article, we have mentioned that the CAR molecule is a key factor that affects the efficacy of CAR-T cell therapy, and understanding its composition and structure is important for preclinical research. Click here to review. However, there are still several obstacles hindering the widespread use of CAR-T therapy.
CAR-T cell therapy has not yet become widely used in cancer treatment due to several limitations. For example, antigen escape and CAR-T cell-related toxicity, such as cytokine release syndrome (CRS) and neurotoxicity, are difficult to avoid. Meanwhile, it remains quite challenging to both efficiently transport CAR-T cells to and infiltrate solid tumors. In addition, the physical characteristics, suppressive cells and inhibitory factors in immunosuppressive tumor microenvironments (TME) further increase the difficulties of technological breakthroughs.
One of the biggest challenges of CAR-T cell therapy is the resistance of tumors to single antigen-targeted CAR-T cells. Initially targeting a single antigen with CAR-T cells can increase immune response, however, some malignant cells in patients show partial or even complete loss of target antigen expression, which is a phenomenon known as antigen escape.
For example, in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) treated with CD19-targeted CAR-T cells, 70-90% showed durable responses, but recent follow-up data suggests a common mechanism of disease resistance, with 19-30% of relapsed patients exhibiting CD19 antigen downregulation/loss of escape. Similarly, in patients with multiple myeloma receiving BCMA-targeted CAR-T cell therapy, downregulation or loss of BCMA expression has also been observed after treatment.
Additionally, similar antigen escape patterns have been observed in solid tumors. For example, case reports of CAR-T cell therapy targeting IL13Ra2 in glioblastoma have shown tumor relapse with reduced expression of IL13Ra2.
One of the challenges of targeting solid tumor antigens is that these antigens are often expressed at varying levels in normal tissues and exhibit heterogeneity of expression within tumor tissue. Therefore, antigen selection is crucial in CAR design to ensure therapeutic efficacy and limit off-target toxicity. In order to expand the clinical application of CAR-T cell therapy in both hematologic malignancies and solid tumors, it is necessary to develop innovative strategies to reduce antigen escape, select antigens that can induce sufficient anti-tumor efficacy, and minimize toxicity at the same time.
Compared with hematological malignancies, the treatment of solid tumors is limited by the inadequate transport and infiltration capability of CAR-T cells. due to the immunosuppressive TME and physical tumor barriers (such as the tumor stroma) that restrict the penetration and mobility of CAR-T cells. The stroma is mainly composed of extracellular matrix (ECM), among which heparan sulfate proteoglycan (HSPG) is the main component that CAR-T cells must degrade in order to enter the tumor.
In tumor microenvironment (TME), immunosuppression is driven by multiple factors: many immunosuppressed cell types that infiltrate within solid tumors, meanwhile, elevated PDL1 level on tumor cells also reduce the anti-tumor activity of immune cells through PD-1 immune checkpoint pathway. Therefore, the combination of CAR-T cells and checkpoint blockade is considered to be the next frontier in immunotherapy, as it provides the two strong elements: CAR-T cell infiltration and PD-1/PD-L1 blockade, to ensure the functional persistence of T cell response.
Although this new immunotherapy is encouraging, it should be recognized that this combination might still not be sufficient to induce T cell infiltration and ensure effective functionality. Therefore, it is necessary to combine CAR-T cell therapy and checkpoint blockade with other immunotherapy strategies to enable T cell infiltration and function in conditions of complex hematological malignancies or solid tumors.
The high toxicity and mortality seen in some cases has prevented CAR-T cell therapy from becoming a first-line treatment. So far, the toxicity of CAR-T cell therapy has been extensively studied in patients treated with the first FDA-approved CD19-targeting CAR-T cell therapy. Nearly all patients with acute lymphocytic leukemia/lymphoma receiving treatment had at least some mild toxicity. Moreover, 23-46% of patients experienced severe cytokine release syndrome and significant T cell expansion.
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are two CAR-T therapy toxicities that require clinical attention. The incidence and severity of these toxicities may depend on the design of CAR, specific targets, and tumor types.
Indeed, the main mechanism underlying CRS is the cytokine storm caused by activation of CAR-T cells. Pathophysiologically, CRS is mediated by IL-6, and thus treatment relies on blocking IL-6 receptor with tocilizumab and corticosteroids. Nevertheless, severe CRS and death can still happen despite this treatment.
As for neurotoxicity, the underlying pathology and mechanisms are not fully understood yet, and IL-6 inhibitors are usually ineffective for CAR-T cell-induced neurotoxicity. To date, there is no approved therapy to prevent neurotoxicity, thus it is essential to optimize CAR engineering and adopt other strategies to mitigate CAR-induced toxicities.
The unique characteristics of solid tumors and their microenvironments pose enormous challenges to CAR-T cell therapy. Therefore, important directions for future development of CAR-T related immunotherapies will include exploring antigens with higher specificity and stronger stimulation, improving safety of CAR-T cells, and formulating reasonable combination treatment plans. In the next section of "CAR-T Cell Therapy" topic, we will discuss innovative strategies on how to break through the current impasse and enhance treatment efficacy of related immunotherapeutic approaches.
Based on years of research experience in oncology, Cyagen can provide comprehensive support for CAR-T/-NK & other cell therapies, including antibody development, CAR virus preparation, immune cell preparation, phenotype detection, as well as cell model and animal model construction, in vitro/in vivo efficacy evaluation, etc.
 Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021 Apr 6;11(4):69. doi: 10.1038/s41408-021-00459-7. PMID: 33824268; PMCID: PMC8024391.