Engineered T-cell therapy has become an important weapon against blood cancers. Aiming to overcome the obstacles that have stalled the utilization of T-cell immunotherapies in acute myeloid leukemia, two research teams have concurrently found a promising solution in one protein target—along with the potential to expand into solid tumors.
Scientists from the Fred Hutchinson Cancer Research Center and a collaboration between Ospedale San Raffaele Scientific Institute in Italy and U.S. biotech Intellia Therapeutics have designed T-cell receptor (TCR)-based cell therapies targeting the WT1 antigen on leukemia cells. The therapies showed strong antitumor effects in cell cultures and in mice, including against cells from a patient who had developed immune evasion, the teams reported in Science Translational Medicine here and here.
Intellia is already developing a WT1-targeted TCR T-cell therapy dubbed NTLA-5001 in a phase 1/2a AML clinical trial. The Fred Hutch team also suggests that targeting WT1 with a TCR T-cell therapy represents a promising approach to treating AML and possibly even solid tumors.
WT1 has been linked to tumor initiation and proliferation in AML, and it’s highly expressed in leukemia cells compared with healthy cells. But it’s not just any part of WT1 the two teams have identified—both teams zeroed in on a specific site on the protein called WT1 37-45.
The Fred Hutch scientists previously devised an engineered WT1 TCR T-cell candidate called TTCR-C4, which targeted the WT1 126-134 site. But a young AML patient developed recurrent disease after receiving the therapy even though functional T cells targeting WT1 persisted during relapse and WT1 was still expressed by the patient’s AML cells.
After investigation, the scientists uncovered a novel mechanism of escape of cancer cells from immunologic targeting. Leukemia cells evaded detection by expressing less of the immunoproteasome, which is required for the presentation of WT1 126-134 to immune cells.
The Fred Hutch team set out to identify alternative WT1s that don’t require a specific type of proteasome. Their screen pinpointed WT1 37-45. Updated TCR-T cells engineered to recognize the new WT1 site successfully killed leukemia cells from the relapsed patient in lab dishes but also reduced the growth of solid tumor cells lines of WT1-expressing pancreatic cancer and breast cancer.
In a mouse model of pancreatic cancer that lacked an immunoproteasome component, the WT1 37-45 TCR-T cells—but not the TTCR-C4 candidate—reduced the tumor burden, the team reported.
As for the San Raffaele-Intellia team, the researchers isolated 19 TCRs for WT1 from healthy donors. A WT1 37-45 TCR showed the strongest binding activity with antigen-presenting elements for T cells. The final TCR T-cell product, perfected with CRISPR-Cas9 gene-editing tools, showed antigen-specific responses and killed AML cells, acute lymphoblastic leukemia cells and brain tumor cells in lab dishes and in mice.
The two studies on WT1 represent the latest efforts toward constructing engineered immune cell therapy to fight AML. California biotech Senti Bio has made a logic-gated CAR-NK cell therapy that aim to more thoroughly kill off AML by recognizing cancer cells expressing either FLT3 or CD33 but avoid potential side effects by steering the therapy away from healthy cells with the endomucin protein. The therapy recently reported promising results in mouse models.
Both the Fred Hutch and the San Raffaele-Intellia teams believe WT1 37-45 represents an attractive target for the development of cell therapies for AML. Because WT1 is expressed inside leukemia cells, it’s beyond the reach of CAR-T cells, which can only recognize cell surface antigens. Besides, TCR signaling promotes T-cell survival, leading to long-term immune memory, necessary for preventing tumor relapse, the San Raffaele-Intellia researchers said in their study.
WT1 is also expressed across several solid tumors, and a lack of immunoproteasome is a feature of limited response to immunotherapy in solid tumors. A WT1 37-45 TCR-T cell therapy could therefore potentially treat those solid tumors as well, the two teams said.
by Angus Liu
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