CAR-T therapy has emerged as a promising strategy in oncohematology, precisely steering immune responses toward specific targets for effective treatment. However, despite its immense potential, several challenges, such as disease recurrence rates, intricate pathophysiology of target neoplasms, prolonged manufacturing times, and high costs, underscore the imperative to persevere in research and innovation within this transformative field.

The origins of CAR-T cell therapy can be traced back to 1987 when Kuwana et al. first introduced the concept of HLA-independent antigen recognition through a chimeric receptor (1, 2). In the early 1990s, Arthur Weiss of the University of California (San Francisco) reported that chimeric receptors containing the intracellular signaling domain of CD3ζ, activated T-cell signaling. This work resulted in the binding of the intracellular domains of CD3ζ to the chimeric receptors to transfer the activation signaling to the T cell (3).

Until then, the chimeric receptor (TCR) was composed of an antibody’s variable region domain and the TCR’s constant region domain. However, transduction exhibited low efficiency due to the necessity of introducing two genes into the same lymphocyte using retroviral vectors to encode the chimeric receptor. In response to this issue, in 1993, Zelig Eshhar, Gideon Gross, and colleagues published the structure of a novel chimeric receptor composed of a single-stranded variable fragment (scFv) derived from an antibody bound to the CD3ζ intracellular complex (4). Both immunologists redirected this research towards the field of oncology (5, 6).

In the mid-1990s, significant progress was made by developing the first clinical trial based on CD8+ T cells modified to express a chimeric receptor structure against a surface antigen present in HIV-infected cells. This work demonstrated that the modified CD8+ T cells effectively identified and eliminated infected cells, showing a lytic capacity of 50-60%. Also, it was described that these ScFv-based receptors had a Major Histocompatibility Complex (MHC)-independent recognition, in contrast to initial cTCRs, suggesting the potential development of universal cell therapy (7). Thus, was born the first T cell designed with the chimeric receptor structure of the products currently marketed, called “T body” (8).

The hypothesis of linking the chimeric receptor to other cells of the immune system such as Natural Killer (NK) lymphocytes was proposed in 1993 to explore its HLA-independent lytic activity (4). This response is mediated by the killer immunoglobulin receptor (KIR) and triggered by detecting reduced inhibitory markers or stress markers on the surface of abnormal cells (9). However, currently, compared to CAR-T cells, CAR-NK cell-based adoptive immunotherapy is generally limited by substantial restrictions prior to large-scale practical implementation. These limitations encompass inadequate proliferation and in vivo activation capacity or limited persistence (10, 11).

In response to the non-sustained activation observed in first-generation CAR-T cells, research from 1995 to 1998 delved into the role of co-stimulatory molecules to enhance lymphocyte activation and CAR-T cell persistence. This concept is grounded in the extrapolation of the theory of dual activation signals observed in T-cell antigenic recognition.

During this period, the research published by Sadelain et al. in 1998 showed evidence that CD28 signaling had a substantial impact on the enhanced survival and proliferation of CAR-T cells and an increase of pro-inflammatory cytokines production when they recognized the target. These findings had significant implications for the potential effectiveness of T-cell therapies (12).

Margo Roberts and Helene Finney were the first to develop a 2nd generation CAR-T therapy (CD28-CARs) and achieved a patent in 1997 (Margo Robert’s patent was filed in February 1995 and Helene Finney’s patent was filed in December 1996) (13–15).

In the 2000s, several research was led to study different costimulatory molecules to improve their antileukemic effect. CAR constructs began to be developed with the 4-1BB molecule (CD137), which appeared to provide CAR-T cells with great persistence in the body (16, 17). These studies with second-generation CAR-T cells (CD137 and CD28) focused on targeting the CD19 antigen, which is specific to the B-lymphoid lineage, especially CLL (18) and ALL (16, 17).

In 2005, considering the studies published on both co-stimulatory molecules, Brenner et al. studied third-generation CAR-T consisting of two costimulatory molecules, CD28 and OX40 to improve antileukemic efficiency (19). However, these studies did not demonstrate a therapeutic benefit, but warnings regarding its use have emerged (20) ( Figure 1 ).

In 2010, a pivotal moment arrived when Steven Rosenberg at the NCI and Carl June and David Porter at the University of Pennsylvania administered CART-19 to a patient with chronic lymphocytic leukemia (CLL), marking a turning point in CAR-T therapy’s trajectory (22).

This therapy underwent a revolution with the case of Emily Whitehead, a 7-year-old diagnosed with acute lymphoblastic leukemia (ALL) refractory to standard treatments. She participated in a phase 1 clinical trial (NCT01626495), receiving an infusion of autologous CTL019, a CAR-T therapy with 4-1BB as a co-stimulatory molecule, similar to the previous studies published in CLL (23). An example of the influence of this case is the foundation created by Emily Whitehead’s family to encourage donations to support oncology research for children’s treatment (24).

Between 2013 and 2014, the first clinical trial results were published and it was not until 2017 that the Food and Drug Administration (FDA) approved Kymriah (tisagenlecleucel) (25) for use in relapsed or refractory ALL after two prior lines for children and young adults up to 25 years old, and Yescarta (axicabtagene ciloleucel) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of treatment. The latter study included DLBCL, primary mediastinal lymphoma, high-grade B lymphoma, and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is an anti-CD19 CAR-T like tisagenlecleucel but differs in the co-stimulatory molecule as it is made up of CD28 rather than 4-1BB (26, 27).

Since that time until now, various regulatory agencies such as the FDA or the European Medicine Agency (EMA) have approved different products for oncohematological pathologies. For instance, Tecartus (brexucabtagene autoleucel) has been approved for mantle cell lymphoma treatment (28), Breyanzi (lisocabtagene maraleucel) for DLBCL treatment (29) or Abecma (Idecabtagene vicleucel) (30) and Carvykti (ciltacabtagene autoleucel) (31) for multiple myeloma treatment. Additionally, tisagenlecleucel and axicabtagene ciloleucel are seeking to expand their indications to follicular lymphoma treatment through the ELARA (32) and ZUMA-5 (33) clinical trials, respectively. These products have been approved for these pathologies in the relapsed or refractory setting after two or more lines of treatment ( Figure 2 ).

Considering the promising results, several pivotal trials of CAR-T products with extensive experience have been published, aiming to administer them in earlier lines of therapy. The ZUMA-7 (34) and ZUMA-12 (35) trials have reported results of administering axicabtagene ciloleucel in the 2nd and 1st line of treatment, respectively.

However, currently, several limitations related to this therapy have been described.

The article has been written by CC and reviewed by MCV, CP, JRR-M, and FP. All authors contributed to the article and approved the submitted version.