Epigenetics Reveals A Difference Between Chronological Age And Biological Age

Given the considerable success of T cell therapy tailored to express chimeric antigen receptors (CARs) addressing the CD19 signal transduction receptor for relapsed and/or refractory large B cell lymphoma (Plum X Metrices, 2019), there are also ways to boost reaction times, maximize substance’s components signaling’s intracellular domain ability and reduce toxicity. Identifying the components of the infusion substance and investigating the etiologies of CAR T cell toxicity impacting patient outcomes is an ongoing area of research.

Supporting studies

Two research, one in Nature Medicine4 and one in Cell5, have recently used multi-dimensional analysis techniques to examine the cell signature of CAR T cell components for reaction and toxicity information4 and classify previously unknown cell populations that could lead to these effects (Parker et al., 2020).

What are CAR T cells?

CAR T cells are genetically engineered T cells to merge the extracellular domain of single-chain vector fragment antibody with the signalling’s intracellular domain of T cell signalling, thereby combining antibody-based specificity with T cell cytotoxicity to enable major complex histocompatibility–independent targeting of tumor antigens.

CAR T cells are usually formed from lymphocytes originating from autologous apheresis samples; hence, the configuration of CAR T cells is specifically personalized to the patient and involves a broad spectrum of heterogeneity, which can lead to the widespread presentation of the cytokine-release syndrome, neurotoxicity (immune effector cell-associated neurotoxicity syndrome) and CAR T cell efficacy.

 

The initial analysis

Initial examination of patients’ apheresis samples and CAR T cell components, primarily due to flow cytometry, identified important phenotypic markers correlated with the patient’s answer. Particularly, markers that show elevated T cell fatigue, contributing to a gradual decline in T cell potency, have been correlated with dysfunctional reactions.

 

Alternatively, the existence of naive or early memory T cells, which may have greater T cell potency, correlates with increased clinical response8, and the loss of these subtypes leads to weak T cell expansion.

 

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These findings demonstrate the significance of T cell phenotypes in tandem with anti-tumor efficacy. Single-cell analysis tools, such as single-cell RNA sequencing (RNAseq), enable detailed investigation that may potentially contribute to the discovery of small, historically undervalued populations that could be clinically important and offer insight into the molecular specifics of why certain people react or have more serious toxicity, while others do not.

 

Outcome

It was found that patients with partial response or progressive disease have shown enrichment of depleted CD8+ T cells, and patients with full response have shown enrichment of memory T cells. Moreover, in those with higher-level illness, the expression of memory-compliant T-cell markers was decreased, which was also associated with bad outcomes (Das et al., 2019).

 

Secondary analysis

A secondary analysis that used a cell-free DNA assay to classify early molecular responses to therapy found a decrease of more than five times in tumor detection by cell-free DNA on day 7 after infusion (relative to the day of infusion) was correlated with enhanced 3-month response. Taking help from the RNAseq dataset, the experimentalists identified that the exhausted T cell phenotype was more abundant in sub-optimal reaction patients who did not fulfil this benchmark than in those who did, further supporting the connection of exhausted T cells with poor response.

 

CAR product and toxicity association

In the end, they utilized their scRNAseq database to establish correlations between the CAR product and toxicity. They found a very small but substantial cell population (254 cells) in the infusion product associated with more extreme neurotoxicity. Based on gene expression and a single-sample set-enrichment study, these cells appeared to be myeloid in origin and expressed essential cytokine and chemokine markers reported to be correlated with cytokine-release syndrome-related neurotoxicity, including IL-1β and CXCL8 (IL-8) (Norelli et al., 2018).

 

Bibliography

Das, R. K., Vernau, L., Grupp, S. A., & Barrett, D. M. (2019, April). Naïve T-cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers. Research Briefs. Cancer Discoveries. 10.1158/2159-8290.CD-18-1314

Norelli, M., Camisa, B., Barbiera, G., Falcone, L., Purevdorj, A., Genua, M., Sanvito, F., Ponzoni, M., Doglioni, C., Cristofori, P., Traversari, C., Bordignon, C., Ciceri, F., Ostuni, R., Bonini, C., Casucci, M., & Bondanza, A. (2018, May 28). Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nature Medicine. Nature Medicine. https://doi.org/10.1038/s41591-018-0036-4

Parker, K. R., Migliorini, D., Perkey, E., Chang, H. Y., Posey, A. D., & Satpathy, A. T. (2020, October 1). Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Cell, 183(1). Cell.com. https://doi.org/10.1016/j.cell.2020.08.022

Plum X Metrices. (2019). Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. The Lancet Oncology, 20(1). ScienceDirect. https://linkinghub.elsevier.com/retrieve/pii/S1470204518308647