Ilaria Michelozzi, PhD, Discusses CAR T-Cell Targeting in AML

Ilaria Marina Michelozzi, PhD, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, London, United Kingdom, discusses therapeutic targeting using chimeric antigen receptor (CAR) T-cells in acute myeloid leukemia (AML).

Transcript

Hi. I'm Ilaria Marina Michelozzi. I am a postdoc in Giustacchini's lab at UCL CH in London.

Today, I'm going to talk about our recent review published last June on cancers, where we dissected the impact of acute myeloid leukemia (AML) on the successful application of chimeric antigen receptor (CAR)-T cells.

CAR T-cells are powerful therapeutic tool, and they are able to recognize and kill cancer cells. They've been successfully applied in the treatment of several hematological malignancies, such as relapsed or refractory acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, their clinical application in AML is still challenging.

There are several factors that are challenging the applicability of CAR T-cells in AML. Some of them are general limitations of CAR T-cell application, such as toxicities, in particular neurotoxicity, and cytokine release syndrome and relapse due to the emergence of cancer cells that do not longer express the target antigen or the durability of the response, the accessibility to the treatment.

There are some other factors that are specifically linked to the AML complex pathobiology, in particular the leukemic stem cell (LSC), and the leukemic bone marrow niche features.

LSC are rare and heterogeneous cells, and they are responsible for AML initiation, maintenance, and relapse. They may reside within the leukemic bone marrow niche, which is leukemic-supportive, hypoxic, immunosuppressive, and chemoprotective microenvironment.

LSC shares several immunophenotypic markers with the normal hematopoietic stem cells and normal tissues. It's very difficult to identify allochemic-specific target that is expressed only on cancer cells and not on the normal counterpart. Consequently, it is very difficult to avoid the so-called on-target off-tumor toxicity of CAR T-cell therapies.

Moreover, LSC are extremely heterogeneous both inter and intraindividually. Indeed, recent studies reported the coexistence in the same patients of different subclones of LSC that are different from a genetic background, and consequently from an immunophenotypic point of view. It's very difficult to identify a unique universal target that is expressed in all the LSC, in all the patients, and in all the AML subsets.

Lastly, the leukemic bone marrow niche with its hypoxic and immunosuppressive nature might affect the CAR T-cell functionality, and so reduce the capability to kill the LSC in the niche. Moreover, several studies highlighted dysfunction of T-cells derived from AML patients probably due to prior chemotherapy or AML intrinsic features. Dysfunctions, in some cases, can lead to incapability or challenges in generating CAR-T cells from this autologous source.

To summarize, there are 3 main factors that are negatively influencing the applicability of CAR T-cells in AML related to AML complex pathobiology—the absence of leukemic-specific target, the absence of a universal target, and the immunosuppressive nature of the leukemic bone marrow niche.

Additionally, we have to remember that the average age of AML patients is 68 years. Patient's age can increase the risks of toxicities related to CAR T-cell therapies.

CAR T-cell study in AML is in its infancy with several preclinical studies and very few early-phase clinical trials that, unfortunately, resulted in unsuccessful or limited success and limited benefits in treated patients.

In our review, we outlined several strategies that can help in overcoming the limitations that I described to you earlier. For instance, the applicability, the use of single-cell technologies, and in particular the most recently multiomics technologies can help in better dissecting the heterogeneity of AML and, consequently, to identify leukemic-specific targets.

It is possible to optimize CAR-T design in order to increase their specificity, safety, efficacy, and also armor these CAR T-cells against the immunosuppressive microenvironment.

Some strategies are currently tested in clinical trials. In general, there are some clinical trials that are currently investigating multitargeted approaches with CAR T-cell therapies in order to overcome AML heterogeneity and to avoid relapse due to clonal selection.

Moreover, there are some clinical trials that are shifting from a universal approach to a more personalized tailored approach. Clinicians are infusing CAR T-cells against specific targets according to the patient-specific AML phenotype.

Lastly, I would like to mention an early-phase clinical trial that is investigating universal and allogeneic CAR T-cells in AML patients. This will be very important in order to bypass the possible limitations in CAR-T cell manufacturing starting from an autologous material.

In light of this, my postdoctoral research revolves around the use of multiomics technology to identify a combination of targets that are specifically expressed on cancer cells and not on the normal counterpart, in order to generate CAR T-cells that can specifically kill malignant cells while sparing the normal ones.