June 16, 2024

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How about patients now after CAR-T cell infusion ten years ago?

How about patients now after CAR-T cell infusion ten years ago?


How about patients now after CAR-T cell infusion ten years ago?

Two of the first cancer patients treated with chimeric antigen receptor-modified (CAR) T cells have been cancer free for a decade. A new study uses single-cell sequencing technology to provide a window into the evolution of their CAR T cells during a decade of remission.


Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, remains “incurable” with standard treatment despite improvements in treatment. Metastasis of CAR T cells targeting tumor cells represents an alternative approach that has shown potential in several cancers.

However, research on the long-term potential of CAR therapy is still limited, and a deep understanding of the durability and stability of elicited T-cell responses is lacking.

A study published in the journal Nature now reports a clinical milestone and investigates the evolution of T cell responses in two CLL patients who achieved remission following CAR therapy in a first-in-human clinical trial in 2010 [1] ].


Both patients were in advanced stages of disease at the time of study entry and had relapsed after multiple rounds of chemotherapy and antibody therapy.

Patients were infused with CAR T cells specific for the human CD19 molecule, which is expressed during B cell development and maintained in cancerous B cells in CLL.

The internal domains of CARs have the 4-1BB costimulatory signaling domain and the CD3ξ signaling domain of the T cell receptor (TCR) [2].

Notably, June and colleagues [1] found that infused CAR T cells were detectable for 10 years in both patients (Figure 1).


How about patients now after CAR-T cell infusion ten years ago?

Figure 1: Two chronic lymphocytic leukemia patients were the first recipients of CAR T cells. In-depth analysis of their blood samples collected over the past decade showed that early expansion of CD8+ and γδ CAR T cells and oligoclonal persistence of activated CD4+ CAR T cells provided a window into CAR T cell evolution.


The fact that these CAR T cells were detectable at all analyzed time points allowed the researchers to isolate them and use single-cell RNA sequencing and molecular characterization tools as well as functional assays to characterize the presence of these CAR-modified cells in the patient’s body.

The opportunity to study anti-cancer immunity with a defined “time 0” is very rare, but in these cases the day of infusion of CAR T cells can be defined as the real starting point.


What conclusions can be drawn from this in-depth descriptive analysis?


First, the data suggest that a “perfect” CAR T cell may not be required to mediate a response, although this may also occur, as the authors demonstrate in the case of a CAR integrated into the TET2 locus, in which the elimination of an intact tumor is driven by the progeny of a single cell with altered epigenetic signatures that keep it in a central memory state.

In contrast, native and CAR T-cell immunity may be more like a symphony of cells, with each cell type playing its part: Initially, CD8+ and γδ T cells expand and produce most of their antitumor activity, then they shrink or fade out, while A subset of oligoclonal CD4+ T cells has formed the predominant form of long-term memory over the years.


Second, the marked early expansion of Helioshi γδ T cells observed in one of the two patients may suggest that this T cell subtype may not be just a passenger, but may be very active.


Third, CD4+ T cell memory clones may also be directly cytotoxic and may be important in eliminating the last tumor cells that became undetectable 6 months after infusion.

Interestingly, this time frame is similar to that in a related report in which acute lymphoblastic leukemia (ALL) clones could not be detected when treated with the same CAR construct in another study.


Fourth, one mechanism by which CD19+ CAR T cells may exist for so long is the continuous production of B cells in the bone marrow, which was also demonstrated by analysis of immunoglobulin heavy chain rearrangements. Interestingly, unlike chronic viral infection or other forms of chronic antigen exposure, CAR T cells did not fail, but maintained their ability to activate, proliferate, and function. A potential explanation for this resistance exhaustion is the embedding of the 4-1BB co-stimulatory domain in the CAR.


Notably, although the CAR T-cell field has experienced rapid clinical development over the past decade, six different approvals have been received in relapsed or refractory hematological malignancies. Including ALL, large cell lymphoma, mantle cell lymphoma, and multiple myeloma — the two patients described here had CLL, which is not among the malignancies for which CAR T cells have been approved.


So far, it is unclear whether the CAR T-cell clonal dynamics observed by June and colleagues [1] also apply to other CLL patients, patients with other diseases treated with the same CAR T construct, or those with other signaling domains CAR. In addition, it will be interesting to investigate how CAR T-cell products infused at pre-specified CD4+ to CD8+ T cell ratios evolve differently.

The CD19 antigen may also be unique because the bone marrow continues to produce early-stage B cells, thereby providing continued antigenic stimulation of CAR T cells.


Another open question in the field is how long CAR T cells need to persist to achieve a “cure” of “incurable” cancers. CAR T cells with the CD28 signaling domain appear to mediate durable remissions in large cell lymphomas with short duration (less than 3 months) [7].

In contrast, CAR T cells targeting multiple myeloma with the 4-1BB signaling domain appear to persist in most patients for at least 6 months, but with a median progression-free survival of less than one year [8].

The research group’s larger study of the same anti-CD19 CAR T product in CLL patients showed that initial T cell phenotype and CAR T cell product predicted to a greater extent than classical prognostic factors in CLL [9] reaction.

However, in large cell lymphoma treated with axicabtagene ciloleucel, a CAR T-cell product with a CD28 signaling domain, results appear to be related to a combination of product attributes, particularly CD8+ T-cell memory signature [10], pre-infusion Inflammation and tumor burden [11].


Additional studies and data maturation from previous registration trials will further illustrate the relationship between CAR T cell signaling domains, CAR T cell persistence and underlying malignancy characteristics and the therapeutic potential of engineered T cells.

June and colleagues’ study provides the first important insights into the persistence, stability , and promises to be a blueprint for future studies of this therapeutic modality across structures and diseases.





How about patients now after CAR-T cell infusion ten years ago?

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