Advancements in Personalized CAR-T Therapy: Comprehensive Overview of Biomarkers and Therapeutic Targets in Hematological Malignancies

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel anticancer therapy using autologous or allogeneic T-cells. To date, six CAR-T therapies for specific B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphomas (NHL), and multiple myeloma (MM) have been approved by the Food and Drug Administration (FDA). Significant barriers to the effectiveness of CAR-T therapy include cytokine release syndrome (CRS), neurotoxicity in the case of Allogeneic Stem Cell Transplantation (Allo-SCT) graft-versus-host-disease (GVHD), antigen escape, modest antitumor activity, restricted trafficking, limited persistence, the immunosuppressive microenvironment, and senescence and exhaustion of CAR-Ts. Furthermore, cancer drug resistance remains a major problem in clinical practice. CAR-T therapy, in combination with checkpoint blockades and bispecific T-cell engagers (BiTEs) or other drugs, appears to be an appealing anticancer strategy. Many of these agents have shown impressive results, combining efficacy with tolerability. Biomarkers like extracellular vesicles (EVs), cell-free DNA (cfDNA), circulating tumor (ctDNA) and miRNAs may play an important role in toxicity, relapse assessment, and efficacy prediction, and can be implicated in clinical applications of CAR-T therapy and in establishing safe and efficacious personalized medicine. However, further research is required to fully comprehend the particular side effects of immunomodulation, to ascertain the best order and combination of this medication with conventional chemotherapy and targeted therapies, and to find reliable predictive biomarkers.

Keywords: CAR-T; EVs; TME; biomarkers; checkpoint inhibitors; hematological malignancies; immunotherapy.

Figure 1

Co-stimulatory and co-inhibitory receptors of CAR-Ts [96], modified. B- and T-lymphocyte attenuator (BTLA), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), lymphocyte-activated gene 3 (LAG-3), T-cell immunoglobulin and mucin domain 3 (TIM-3), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), killer cell lectin like receptor G1 (KLRG-1), inducible T-cell co-stimulatory (ICOS), glucocorticoid-induced TNFR-related protein (GITR), chimeric antigen receptor (CAR), tumor-associated antigen (TAA).

Figure 2

Biomarkers in CAR-T therapy. Programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), T-cell immunoglobulin and mucin domain 3 (TIM-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), lymphocyte-activated gene 3 (LAG-3), chimeric antigen receptor T-cell (CAR-T), interleukin (IL), tumor growth factor $\beta$ (TGF-$\beta$), myeloid-derived suppressor cells (MDSC), interferon $\gamma$ (IFN-$\gamma$), T regulatory (Treg).

Figure 3

EVs as biomarkers in CAR-T therapy. Programmed cell death protein 1 (PD-1), chimeric antigen receptor (CAR), Fas ligand (FasL), TNF-related apoptosis-inducing ligand (TRAIL), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4).

Figure 4

The drugs target co-inhibitory molecules that regulate the exhaustion and senescence of CAR-Ts. Programmed cell death protein 1 (PD1), cytotoxic T-lymphocyte-associated protein-4 (CTLA4), T-cell immunoglobulin and mucin domain 3 (TIM-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), lymphocyte-activated gene 3 (LAG-3).