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CD70 Targeted Chimeric Antigen Receptor (CAR) T-Cells for Acute Myeloid Leukemia (AML)

Rational chemical and genetic modifications enhance avidity and function of CD70-directed CAR T-cells for acute myeloid leukemia

Maus Lab

Executive summary

Marcela V. Maus, MD, PhD, and Mark Leick, MD, have devised a novel design for a Chimeric antigen receptor (CAR) T-cell therapy that targets CD70 for treating acute myeloid leukemia (AML). CD70 has an extremely restricted expression on normal tissues but has marked overexpression in a number of cancer types, including AML. CAR T-cell therapy has revolutionized the treatment of some hematologic malignancies, but myeloid diseases remain a significant challenge.

The inventors designed a novel structure of the CAR, recognizing that the natural human binder to CD70 gets cleaved off the extracellular portion of the CAR. By making a series of deletions and substitutions to the hinge domain, they identified a design that was not subject to cleavage. This new design bound to tumors more tightly and was more effective in killing AML tumor cells in vitro and in vivo. The inventors also demonstrated that activity of this CAR is augmented by the addition of azacitidine (AZA), an FDA approved hypomethylating agent already extensively used to treat myeloid malignancies, to increase CD70 target antigen density on AML tumor cells.

Drs. Maus and Leick found that CD70 targeted CAR T-cells are effective at eliminating AML in vitro and in vivo models, AZA synergizes with CD70 CAR T-cells in vivo against AML via upregulation of CD70 protein, and CD70 CAR T-cells maintain effector functions despite exposure to AZA. In sum, the inventors demonstrated durable clearance of tumor in an exceptionally aggressive tumor model with this tandem approach.

Unmet need

Each year in the United States, more than 20,000 people of all ages are diagnosed with AML. The 5-year survival rate for people 20 and older with AML is 26%.

AML is typically treated with intensive chemotherapy, but not all patients are eligible for toxic treatments. Treatment of AML had changed little over 50 years since the advent of intensive “induction” cytotoxic chemotherapy.

There is a high need for a more effective and less toxic treatment for AML, which can be met by using CD70-directed CAR T-cells. Because AML affects a wide age range, there is a need for treatments for the elderly and treatments that reduce relapse.


Marcela Maus, MD, PhD

Dr. Maus is the director of the cellular immunotherapy program at the Mass General Cancer Center. Dr. Maus is also an associate professor at Harvard Medical School, an associate member of the Broad Institute of Harvard and MIT, and an associate member of the Ragon Institute of MGH, MIT, and Harvard. She has more than 20 years of basic laboratory and translational research experience. Leading multidisciplinary teams of scientists and clinicians, she has successfully opened trials of genetically modified T cells in hematologic malignancies, as well as a variety of solid tumors.

Dr. Maus received her BS from the Massachusetts Institute of Technology, and her MD and PhD degrees from the University of Pennsylvania. Dr. Maus trained in internal medicine at the University of Pennsylvania and in hematology and medical oncology at Memorial Sloan Kettering and is board-certified in these three disciplines.

Mark Leick, MD

Dr. Leick is an attending physician at the hematopoietic cell transplant and cell therapy program at Mass General Hospital. He is also a postdoctoral research fellow at the Maus Lab, led by Dr. Marcela Maus, where he studies novel chimeric antigen receptor (CAR) T-cell design and clinical trials. Dr. Leick is an instructor in medicine at Harvard Medical School.

Dr. Leick received his BE and BS from the University of Arizona, Tucson, and his MD from Georgetown University. He completed his residency at Johns Hopkins Hospital and his fellowship at the Dana-Farber Cancer Institute. He is board-certified in both internal medicine and medical oncology.

Jennifer Finefield, PhD
Director, Business Development & Licensing, Mass General Brigham Innovation

Rationale of disease


AML is a rare type of cancer of the blood and bone marrow with excess immature white cells. These abnormal white blood cells leave less room for healthy cells (red blood cells, white blood cells, and platelets), resulting in easy bleeding, infections, and anemia. AML is a liquid cancer so it does not produce tumors. However, AML is aggressive and can spread quickly to the lymph nodes, spine, brain, liver, spleen, and other organs. If left untreated, AML can be life threatening. The 5-year survival rate of AML is 28.3%.

AML is most common among men and older adults, with the average age of diagnosis being 68. Genetic disorders, blood disorders, and exposure to hazardous chemicals through smoking or other means are common causes of AML. AML can be diagnosed through blood tests, a bone marrow aspiration or biopsy, a spinal tap, and genetic testing. The most common treatment for AML is chemotherapy drugs. Other treatment options include bone marrow transplants and clinical trials.

Unmet needs

Although AML is a rare form of cancer, it is the second most common form of leukemia diagnosed in children and adults. Each year in the United States, over 20,000 people of all ages are diagnosed with AML. The proportion of leukemia cases that are AML has increased by over 5% from 1990 to 2017, increasing the need for new AML treatments. 

While AML was uniformly fatal half a century ago, intensive chemotherapy now cures 40% of adults. This is a substantial improvement, but there remains a significant unmet clinical need for older and relapsed and refractory patients where fewer than 10% of patients are cured. AML represents a unique burden because it affects people of various ages, involves extensive time in the hospital, is associated with high rates of infection and complications, and requires the need for stem cell transplants (bone marrow).

Many AML patients are not eligible for intensive chemotherapy. There is an unmet need for more effective and less toxic treatments that improve quality of life from disease. AML patients also have a high rate of relapse so treatments that reduce relapse are in high demand.


Background and proof of concept

With the development of CAR T-cell therapy, patients with advanced cancers of the blood have new option for treatment. However, the use of CAR T therapy for AML has been challenging for myriad reasons, including lack of a suitable antigen and “off-target” effects resulting from the killing of healthy normal myeloid cells, as well as AML cells. 

Through their research, Drs. Maus and Leick devised a CAR T construct directed against CD70, an antigen present in larger numbers on AML cells than on healthy myeloid cells. When used as a solo therapy, the CAR T was only moderately effective against AML in animal models. However, combining it, in vitro and in vivo, with FDA-approved AZA dramatically increased the number of CD70 antigens on the cancer cell surfaces, rendering the CD70 targeted CAR T therapy more effective. Furthermore, due to a series of deletions and substitutions within the CAR construct, the inventors created a CAR T therapy that bound more tightly to the tumor and was not susceptible to decapitation or cleavage.    


The inventors generated a CD70 targeted CAR T-cell construct and implemented azacitidine (AZA) to improve potency. This construct was based on a previously optimized design against solid tumors. To test this therapy in liquid cancer (AML), the inventors used in vivo and in vitro mouse models.

The inventors found that CD70 targeted CAR T cells are effective at eliminating models of AML in vivo and in vitro and maintained effector functionality in the presence of AZA.

Competitive advantages

This is a completely novel CAR T-cell treatment for AML. The use of this uniquely designed CD70-directed CAR T-cells has not been documented elsewhere. The use of this novel construct to target CD70 in combination with AZA represents a promising therapy against an exceptionally difficult disease to treat with existing strategies. This novel treatment for AML offers a safer and more effective treatment than chemotherapy and helps reduce the risk of relapse.

The global acute myeloid leukemia (AML) therapeutics market is expected to reach $976.2 billion by 2026. AML is a rare blood cancer, but there are over 20,000 new diagnoses of AML each year, and it is the second most common type of leukemia diagnosed in adults and children.

More generally, the global market for blood cancer therapeutics should grow from $38.5 billion in 2018 to $64.8 billion by 2023 at a compound annual growth rate (CAGR) of 11% from 2018 to 2023.

Leick MB, Silva H, Scarfò I, Larson R, Choi BD, Bouffard AA, Gallagher K, Schmidts A, Bailey SR, Kann MC, Jan M, Wehrli M, Grauwet K, Horick N, Frigault MJ, Maus MV. Cancer Cell. 2022 May 9;40(5):494-508.e5. doi: 10.1016/j.ccell.2022.04.001. Epub 2022 Apr 21.

U.S. Provisional Application: 62/900,826

PCT Application: PCT/US2020/051018

U.S. Patent Application: 17/761,131

EP Patent Application: 20865730.4