ASGCT20: Intellia Presents Data on Two of its CRISPR-Based Novel Therapeutic Candidates
By Ruchi Jhonsa, Ph.D.
At the 23rd Annual virtual Meeting of the American Society of Gene and Cell Therapy, Intellia Therapeutics, a leading genome editing company, presented some key data pertaining to the developments of its novel drug candidates NTLA-5001 and NTLA-2002 against acute myeloid leukemia and hereditary angioedema respectively.
Acute Myeloid Leukemia Treatments
Acute myeloid leukemia (AML) is the cancer of the blood and bone marrow that can be fatal if left untreated. Standard treatment involves cycles of intensive chemo followed by stem cell transplantation. While chemotherapy is successful in treating the disease, the cancer has a high probability of relapse. Currently, immunotherapy is emerging as an attractive strategy for treating relapsing cancers.
A type of immunotherapy known as T cell receptor (TCR) gene therapy has gained a lot of popularity since its conception. In physiology, T cells recognize antigen with their antigen receptor called T cell receptor or TCR. However, unlike antibodies that recognize antigen directly, TCRs need antigen to be processed by antigen-presenting cells (APC) before they can recognize it. These processed antigens are presented on the surface of APCs in complex with major histocompatibility complex (MHC), also known as HLA in humans.
T cells play an essential part in cell-mediated immunity, and their role has inspired the development of several strategies to genetically modify T cells including TCR gene therapy. This standard therapeutic mode transforms TCRs to specifically recognize cancer antigens and attack the cancer cells. However, the major challenge with standard therapy is the presence of endogenous TCR on the T cells. Transgenic TCRs are expressed on the same cell as endogenous TCRs, which causes mispairing of the two. This leads to a reduction in the activity and surface expression of the transgenic TCR.
NTLA-5001: A Novel Cell Therapy Candidate against AML
Dr. Aaron Prodeus, senior scientist at Intellia Therapeutics, presented an immunotherapy strategy that overcomes the challenges of standard therapy. Immunotherapy candidate, NTLA-5001 is an engineered TCR T cell therapy that targets Wilms’ tumor (WT1) intracellular antigen overexpressed in Acute myeloid leukemia. The candidate was produced using sequential gene-editing technology that enables multiple gene edits using CRISPR/Cas9 without the generation of any genomic errors.
According to the data, the technology could knockout three genes with up to >98% efficiency. NTLA-5001 is unique and specific to AML as it lacks endogenous TCR and has a transgenic TCR against the WT1 antigen inserted in its place. Dr. Aaron reported that the deletion of endogenous TCR was achieved in the T cells with >99% efficiency, and the insertion of transgenic TCR was seen in 50-70% of the cells. This engineered T cell population developed using gene-editing technology was found to be much better in its expansion capacity than the standard therapy. Besides, it had a desirable early stem cell memory phenotype, improved activity against WT1 expressing tumor cell lines, and higher long term proliferative capacity, all of which are important from a therapeutic standpoint. This improvement is beneficial as it can deliver the T cell treatment to the patients in a short time with a chance of better outcomes than existing immunotherapies.
Intellia is all set to investigate NTLA-5001 in clinical trials while focusing on preclinical studies exploring the potential for targeting WT1 in solid tumors. The company plans to submit an IND for the treatment of AML in the first half of 2021. “The data being presented at the meeting validate Intellia’s approach of reducing AML tumor cell blasts, and our plans to enter the clinic with NTLA-5001 next year,” said Intellia President and CEO John Leonard, M.D.
NTLA-5001 Shows Efficacy in Mouse Models
Although T cell therapy based on the modification of TCR has been effective, finding the exact tumor-specific TCR is a challenge. A collaborative study led by a group of researchers from Ospedale San Raffaele, Italy and Intellia Therapeutics identified TCR specific to Wilms Tumor 1 antigen, a tumor-associated antigen overexpressed in a variety of hematological and solid tumors.
T cells harboring these WT-1 specific TCR were tested in a mouse model for their efficacy. To identify TCRs specific to WT1, the researchers extracted T cells from 14 healthy donors and successfully expanded them by repetitive stimulation using APCs expressing WT1 peptide. The product of this experiment was an enriched population of T cells expressing TCR against the WT1 antigen.
To further refine the population and test their target specificity, these enriched T cells were grown together with antigen-expressing cells and leukemia cells. The group identified 21 different alpha-beta chain pairs that were capable of recognizing antigen WT1 along with different antigen-presenting HLA proteins. To verify the efficacy of these TCRs against tumor antigens, they were introduced in a T cell, which was already stripped of its endogenous TCR. This resulted in a T cell population expressing just the transgenic TCR.
Researchers observed that these modified T cells had a significant therapeutic effect in vivo. These cells were able to decrease the AML tumor burden. Additionally, they did not generate any graft versus host disease, which could lead to an attack on the patient’s healthy cells. These data show that Intellia’s engineered TCR T cell approach is active in a challenging model of systemic AML.
NTLA-2002, an Investigational Gene-Editing Therapy Candidate for Treating HAE
Affecting 1 in 50,000 patients, hereditary angioedema (HAE) is a life-threatening disorder characterized by recurrent episodes of swelling in various parts of the body. This disorder is a result of an inactivating mutation in the C1 esterase inhibitor protein, which is a key regulator of the kallikrein enzyme responsible for the conversion of kininogen to bradykinin. In the absence of the inhibitor, the level of kallikrein rises rapidly in the plasma causing the uncontrolled synthesis of bradykinin. Bradykinin is a potent vasodilator that increases the permeability of blood vessels, which results in an outflow of water into the tissue leading to swelling. The current model of therapy employs the administration of the C1 inhibitor every 2 weeks, increasing the burden on the patient and the physician.
Leveraging their modular platform for CRISPR delivery, scientists at Intellia therapeutics have developed a single course one-time CRISPR based therapy for the treatment of HAE. This treatment employs CRISPR based gene editing delivered through Intellia’s modular nanoparticle-based platform to knock out the KLKB1 gene in the liver, which will reduce kallikrein activity and prevent excessive buildup of bradykinin.
Using a mouse model that harbors the human KLKB1 gene in place of the mouse gene, researchers showed that their lead CRISPR candidate could reduce KLKB1 mRNA as well as protein in the serum. The results with the mouse model were also observed in the non-human primate model, where more than 70% of the KLKB1 gene was edited using the lead candidate.
Although studies are still ongoing, preliminary observation reveals that a one-time dosage of NTLA-2002 can lead to sustained downregulation of kallikrein for at least 6 months. With the positive results for NTLA-2002, Intellia finalized it as their lead HAE development candidate last week. Excited by the developments, the company is planning to submit regulatory filings towards the end of next year.
Dr. Leonard said, “We are also pleased to present data that support our recently announced HAE development candidate, NTLA-2002, Intellia’s second systemic therapy employing our in vivo knockout approach and modular delivery platform.”
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