Blood Adv. 2022 July 26;6(14)4185-4195.
Our immune system is a complex organization of lymphocytes, myeloid cells (granulocytes, macrophages, dendritic cells), complement factors, cytokines, and other chemical mediators, which all work together to fend off disease and infection. There are two distinct classes of lymphocytes: B-cells and T-cells, which are vitally important for our immune defense. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), the most common adult form of leukemia, is a B-cell malignancy arising from the B-cell lymphocytes when a mutation or mutations trigger a malignant clone to develop. It is important to understand that CLL / SLL causes dysfunction of the B-cells and the CLL / SLL cells negatively impact T-cells as well, and this dual hit causes an overall dysregulation of the immune system.
The most common T-cells are CD4 cells, also known as T-helper cells, and CD8 cells, also known as T-killer or cytotoxic T-cells. A promising CLL / SLL treatment currently being studied in clinical trials for CLL / SLL is a T-cell-based therapy known as chimeric antigen receptor (CAR) T-cell therapy. This process involves removing T-cells from a patient with CLL / SLL, attaching a protein molecule to the T-cells enabling them to seek out and kill the malignant cells, and then infusing them back into the patient. To learn more about CAR-T therapy, click here:
Understanding the metabolic pathways which cause T-cell dysfunction and finding ways to restore their function is an important step to further improve the efficacy of T-cell-based therapies. Prior research has found that CLL / SLL negatively impacts CD8 T-cells by impeding the metabolic pathways controlling cell maintenance and growth. However, how CLL / SLL cells impact CD4 T-cells is unclear. Therefore, understanding if CD4 T-cells are also affected in the same way as other T-cells and whether targeted CLL / SLL therapies can restore metabolic pathways and improve T-cell function is an important next step in developing effective treatment for this disease and is the focus of this article.
- The researchers used complex techniques to study intricate metabolic pathways of CD4 T-cells required for cellular activation, proliferation, and mitochondrial fitness.
- Samples of peripheral blood from untreated CLL patients and healthy donors were compared to study the metabolic impact of CLL cells on the CD4 T-cells.
- Samples of peripheral blood from 6 CLL patients entered in the phase 2 HOVON 139/GIVE trial were obtained before treatment was initiated and after treatment was completed to study the effect of targeted therapy on CD4 T-cell function.
- HOVON 13/GIVE was a 14-month trial divided into 30-day cycles. The protocol initiated with two cycles of obinutuzumab (a monoclonal anti-CD20 antibody) induction, followed by obinutuzumab in combination with venetoclax (a BCL-2 inhibitor) for cycles 3-8, and then venetoclax alone for cycles 9-14.
- Undetectable minimal residual disease at 1/10,000 measured B-cell lymphocytes was achieved in the peripheral blood in 88% and the bone marrow in 79% of the patients in the clinical trial following the treatment.
- CD4 T-cells from untreated CLL patients were exhausted. In addition, they had metabolic restrictions in glucose metabolism resulting in impaired T-cell activation, proliferation, and decreased mitochondrial fitness.
- Removal of CLL cells from peripheral blood samples in the laboratory resulted in the restoration of metabolic pathways and function of CD4 T-cells.
- Treatment with venetoclax during the clinical trial likewise restored CD4 T-cell metabolic pathways, function, activation, and proliferation.
- Venetolcax also normalized the proportion of Treg cells, a type of T-cell with an immunosuppressive effect in CLL / SLL.
The research shows that CD4 T-cells have plasticity (ability to be changed) and recovery, which can be used to advantage in autologous (from self) T-cell-based treatment. In addition, venetoclax restored CD4 T-cell function by depletion of CLL cells, raising the question of whether CAR T- therapy’s efficacy can be improved with this agent’s addition. The study authors also hypothesize that other targeted treatments that eliminate CLL cells may have a similar effect.
This raises hopes that the immune dysfunction so prominent in CLL / SLL patients can be improved or even eliminated when treatment kills off nearly all the cancer cells and their immunosuppressive influence.
Additional study is needed to define better the processes through which CLL cells cause the alterations in the metabolic pathways of the CD4 T-cells. Finding these mechanisms will help to develop a pharmacologic intervention to block this effect.
Finally, the study also raises the question of whether CAR T-cells can be genetically modified to improve the cellular function of the CD4 T-cells.
You can read the full research article here: Depletion of CLL cells by venetoclax treatment reverses oxidative stress and impaired glycolysis in CD4 T cells.
We share in this journey together.
Kim Davidson, MD
CLL patient and physician