New biomarkers for early prediction of CAR-T cell therapy response

The MedUni Vienna research team has discovered a highly effective biomarker for clinical response to CAR-T cell therapy, describing the prerequisites
for optimizing the treatment of lymphoma with this novel therapy.
The current findings are an important step
towards optimizing this promising treatment.
The results of this study were recently published in the top journal Frontiers in Immunology
.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of
lymphoma (non-Hodgkin lymphoma).
The 5-year survival rate is now between
55% and 64%.
However, patients who relapse early or do not respond to combination antibody chemotherapy have a worse
prognosis.

In recent years, a new and very effective treatment modality has emerged: CAR-T cells
.
In this therapy, the body's own lymphocytes are extracted and equipped with lymphoma-specific chimeric T cell receptors (CAR = chimeric antigen receptors), which are amplified and returned to the patient
.
Due to the expression of chimeric T cell receptors, T cells are transformed into killer cells and, in the best case, permanently eliminate lymphomas in
the patient's body.
Although this therapy is highly effective when CAR-T cells respond to lymphoma cells and allows patients to survive for a long time; Unfortunately, it is not effective
for all patients.

In their clinical study, the scientists started with the starting point of CAR-T cell production: the nature of
the patient's own T lymphocytes (T cells).
In the process, they found that lymphoma patients often lack T lymphocytes (T-cell lymphopenia).

Since lymphopenia is often accompanied by an increase in "depleted" T cells, this study began to measure the number of
these cells.
In fact, in a subset of patients, exhausted T cells increased
significantly.
Such depleted T cells are usually only found
in patients with chronic inflammation.

Based on these observations, the research team led by Nina Worel (Transfusion Medicine) and Ulrich Jäger (Hematology), in collaboration with Winfried Pickl's team (Institute of Immunology), created the basis for dividing
patients into groups with high and low probability of responding to CAR-T cell therapy.

Study leader Winfried Pickl said: "Our study shows how important the nature of T cells is to the production of CAR T cells, and in a significant proportion of patients, depleted T cells can be found to pose a problem
for subsequent CAR T cell therapy.
Our observations of different modes of action of depleted T cells used as starting materials for CAR T cell production show that the degree of differentiation has no negative effect on CAR-T cells directly killing cancer cells, but it does have a negative effect
on leukemia cell-dependent growth and factor production by CAR T cells.
This suggests that depleted CD27negCD28neg-CAR-T cells may not survive longer in patients, which may limit their long-term efficacy
.
”

In summary, Pickl noted, "The low differentiation (depletion) of CD3^posCD27^{neg CD28neg-T} cells at leukocyte isolation represents a novel blood biomarker that can be used even before CAR-T cells begin production and infusion, and predict patient response
to CAR-T cell therapy.
" 。 Removing CAR-T cells from leukocyte isolation products before production begins can significantly improve the success rate of treatment, even in patients with poor initial conditions
.
”