Chimeric antigen receptor (CAR) T and CAR NK cell therapies opened new avenues for cancer treatment. Although original successes of CAR T and CAR NK cells for the treatment of hematological malignancies were extraordinary, several obstacles have since been revealed, in particular their use for the treatment of solid cancers. The tumor microenvironment (TME) is competing for nutrients with T and NK cells and their CAR-expressing counterparts, paralyzing their metabolic effective and active states. Consequently, this can lead to alterations in their anti-tumoral capacity and persistence in vivo. High glucose uptake and the depletion of key amino acids by the TME can deprive T and NK cells of energy and building blocks, which turns them into a state of anergy, where they are unable to exert cytotoxic activity against cancer cells. This is especially true in the context of an immune-suppressive TME. In order to re-invigorate the T, NK, CAR T and CAR NK cell-mediated antitumor response, the field is now attempting to understand how metabolic pathways might change T and NK responses and functions, as well as those from their CAR-expressing partners. This revealed ways to metabolically rewire these cells by using metabolic enhancers or optimizing pre-infusion in vitro cultures of these cells. Importantly, next-generation CAR T and CAR NK products might include in the future the necessary metabolic requirements by improving their design, manufacturing process and other parameters. This will allow the overcoming of current limitations due to their interaction with the suppressive TME. In a clinical setting, this might improve their anti-cancer effector activity in synergy with immunotherapies. In this review, we discuss how the tumor cells and TME interfere with T and NK cell metabolic requirements. This may potentially lead to therapeutic approaches that enhance the metabolic fitness of CAR T and CAR NK cells, with the objective to improve their anti-cancer capacity.

The classification of peripheral T-cell lymphomas (PTCL) is constantly changing and contains multiple subtypes. Here, we focus on Tfh-like PTCL, to which angioimmunoblastic T-cell lymphoma (AITL) belongs, according to the last WHO classification. The first-line treatment of these malignancies still relies on chemotherapy but gives very unsatisfying results for these patients. Enormous progress in the last decade in terms of understanding the implicated genetic mutations leading to signaling and epigenetic pathway deregulation in Tfh PTCL allowed the research community to propose new therapeutic approaches. These findings point towards new biomarkers and new therapies, including hypomethylating agents, such as azacytidine, and inhibitors of the TCR-hyperactivating molecules in Tfh PTCL. Additionally, metabolic interference, inhibitors of the NF-κB and PI3K-mTOR pathways and possibly novel immunotherapies, such as antibodies and chimeric antigen receptors (CAR) directed against Tfh malignant T-cell surface markers, are discussed in this review among other new treatment options.

Background & aims: In CML, Leukemic Stem Cells (LSCs) that are insensitive to Tyrosine Kinase Inhibitors are responsible for leukemia maintenance and relapses upon TKI treatment arrest. We previously showed that downregulation of the BMI1 polycomb protein that is crucial for stem/progenitor cells self-renewal induced a CCNG2/dependent proliferation arrest leading to elimination of Chronic Myeloid Leukemia (CML) cells. Unfortunately, as of today, pharmacological inhibition of BMI1 has not made its way to the clinic. Methods: We used the Connectivity Map bioinformatic database to identify pharmacological molecules that could mimick BMI1 silencing, to induce CML cell death. We selected the bis-biguanide Alexidin (ALX) that produced a transcriptomic profile positively correlating with the one obtained after BMI silencing in K562 CML cells. We then evaluated the efficiency of ALX in combination with TKI on CML cells. Results: Here we report that cell growth and clonogenic activity of K562 and LAMA-84 CML cell lines were strongly inhibited by ALX. ALX didn’t modify BCR::ABL1 phosphorylation and didn’t affect BMI1 expression but was able to increase CCNG2 expression leading to autophagic processes that preceed cell death. Besides, ALX could enhance the apoptotic response induced by any Tyrosine Kinase Inhibitors (TKI) of the three generations. We also noted a strong synergism between ALX and TKIs to increase expression of caspase-9 and caspase-3 and induce PARP cleavage, Bad expression and significantly decreased Bcl-xL family member expression. We also observed that the blockage of the mitochondrial respiratory chain by ALX can be associated with inhibition of glycolysis by 2-DG to achieve an enhanced inhibition of K562 proliferation and clonogenicity. ALX specifically affected the differentiation of BCR::ABL1-transduced healthy CD34⁺ cells but not of mock-infected healthy CD34⁺ control cells. Importantly, ALX strongly synergized with TKIs to inhibit clonogenicity of primary CML CD34⁺ cells from diagnosed patients. Long Term Culture of Initiating Cell (LTC-IC) and dilution of the fluorescent marker CFSE allowed us to observe that ALX and Imatinib (IM) partially reduced the number of LSCs by themselves but that the ALX/IM combination drastically reduced this cell compartment. Using an in vivo model of NSG mice intravenously injected with K562-Luciferase transduced CML cells, we showed that ALX combined with IM improved mice survival. Conclusions: Collectively, our results validate the use of ALX bis-biguanide to potentiate the action of conventional TKI treatment as a potential new therapeutic solution to eradicate CML LSCs

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma characterized by poor clinical outcomes following conventional CHOP-based chemotherapy and the lack of effective disease-specific therapeutic options. The disease finds its origin in CD4 follicular helper T (Tfh) cells and is driven by recurrent genetic alterations, including mutations in TET2, RHOA, DNMT3A, and IDH2. Despite the rarity of AITL, preclinical models have been fundamental in elucidating disease pathogenesis, identifying key molecular vulnerabilities and providing platforms for the evaluation of novel therapeutic strategies. These studies have highlighted multiple targetable pathways, including aberrant mTOR, T-cell receptor and NF-κB signaling. Additionally, widespread epigenetic alterations in the neoplastic T-cells were uncovered due to mutations in epigenetic modifiers in AITL. More recently, metabolic reprogramming has emerged as an additional therapeutic vulnerability, revealing a strong dependence of AITL cells on mitochondrial respiration and lipid metabolism, particularly the choline metabolic pathway. Advances in the understanding of AITL biology have also accelerated the development of immunotherapeutic strategies. Monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown encouraging preclinical and early clinical activity. Of note, the first preclinical results on an in vivo CAR-T-cell approach for AITL are reported. Here we provide a broad overview of AITL, discussing its biological features, pathogenesis, preclinical models, current treatment landscape, and recent advances in therapeutic approaches.