Boosting the immune system to fight blood tumors

A group of researchers coordinated by Giulia Casorati, head of the Experimental Immunology Unit of IRCCS Ospedale San Raffaele, successfully tested in a preclinical model of the diseases a new therapeutic approach to treat blood cancers (ALL and AML) by engineering T lymphocytes from healthy donors. The immune cells are genetically modified to introduce a TCR receptor capable of recognizing CD1c molecules (specifically expressed on blood cells) associated with a particular lipid antigen (mLPA), which is overexpressed in tumors.

The novelty of the study lies in the universality of the complex formed by CD1c and mLPA, a sort of key-lock mechanism that is identical in all individuals: the TCR identified can thus recognize tumor cells in any patient, without histocompatibility barriers among donor and recipient. The results obtained by researchers – so far only on experimental models of acute leukemia – show how these modified T lymphocytes significantly slow down disease progression without affecting healthy host tissues.

The study, published in Nature Communications, was made possible by funding from the AIRC Foundation for Cancer Research, Worldwide Cancer Research and the Leukemia Lymphoma Society.


Cellular immunotherapy for acute leukemias

Acute leukemias are a heterogeneous group of blood cancers caused by the uncontrolled proliferation of hematopoietic cells and can affect both children and adults. The rate of disease relapse is still very high in the most aggressive forms of leukemia, requiring the identification of more effective therapies than the currently available.

The most advanced frontier in this research field is represented by cellular immunotherapy, which consists of infusing patients with T lymphocytes (previously harvested from a healthy donor), genetically modified in the laboratory with a CAR or TCR receptor to better recognize tumors. In particular, TCR receptors are usually capable of recognizing tumor antigens expressed by HLA molecules, that are present on every cell surface.

“The limitation of this strategy is that HLA molecules are extremely polymorphic, differing from one individual to another, so you would need many different TCRs to use depending on the type of HLA expressed by the patient. The optimal situation would be to have a universal ready-to-use TCR, that recognizes all tumor cells regardless of the HLA barrier,” explains Michela Consonni, first author of the study.


The new strategy proposed by San Raffaele

Researchers at San Raffaele identified a possible alternative strategy: modifying human T lymphocytes with a universal TCR that enables them to recognize the lipid antigen mLPA presented by CD1c molecules, which are identical in all individuals and expressed only in blood cells.

“Engineering T lymphocytes with this receptor has considerable advantages: the first concerns the universality of this therapeutic approach, which makes it possible to target all blood cancers expressing the CD1c molecule. The second is related to the fact that the CD1c molecule is exclusively expressed by cells of hematopoietic origin, so there is no risk of directing lymphocytes – armed with the TCR specific for the mLPA lipid – against the patient's healthy tissues, causing Graft-versus-Host Disease”, specifies Giulia Casorati, study coordinator.

“The third but no less important aspect is that, from a metabolic point of view, mLPA is necessary for the tumor cell grows: healthy cells, therefore, express much less of it and are thus not attacked and eliminated by the engineered T lymphocytes”. After modifying and enhancing the immune system cells in vitro, the research group tested their efficacy on experimental models of acute leukemia, showing that they were able to delay disease progression and inhibit tumor growth.

The study explores a never described strategy: the approach could be potentially used to treat all leukemia patients expressing CD1c target molecules. "We are now investigating some important aspects that will improve the safety and efficacy of this technique. In the end, we hope to develop new alternative immunotherapeutic strategies that can complement existing ones, essential to expand the options available for patients who relapse," Casorati concludes.