Photo credit: Bryan Choi, MD, PhD; Mark Leick, MD; and Marcela Maus, MD, PhD
Rational chemical and genetic modifications enhance avidity and function of CD70-directed CAR-T-cells for acute myeloid leukemia
Marcela Maus, MD, PhD and Mark Leick, MD at the Massachusetts General Hospital have devised a novel CAR T cell therapy that targets the checkpoint inhibitor CD70 for the treatment of acute myeloid leukemia (AML). CD70 is found on antigen-presenting cells and activated T cells and is upregulated in AML and other cancers. CD70 has an extremely restricted expression on normal tissues but marked overexpression in a number of cancer types, including AML. Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, but myeloid diseases remain a significant challenge. AML is particularly difficult to treat with CAR T cell therapy possibly due to its low tumor mutational burden coupled with an immunosuppressive microenvironment. The inventors demonstrated that the activity of this CAR is augmented by the addition of azacytidine (AZA), an FDA-approved hypomethylating agent already extensively used to treat myeloid malignancies, to increase target antigen density presenting a viable therapeutic path for patients intolerant of intensive therapy. Drs. Maus and Leick found that CD70 targeted CAR-T cells are effective at eliminating models of AML in vivo and in vitro, 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 tumors in an exceptionally aggressive tumor model with this tandem approach.
Each year in the United States, over 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 fifty 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. Since AML effects a wide age range, there is a need for treatments for the elderly and treatments that reduce relapse.
Marcela Maus, MD, PhD
Marcela Maus, MD, PhD is the Director of the Cellular Immunotherapy Program at the Mass General Cancer Center. She is an Assistant 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. Marcela has over 15 years of basic laboratory research experience and is board certified in internal medicine, medical oncology, and hematology, with particular clinical training in melanoma, myeloma, and bone marrow transplants. Leading multidisciplinary teams of scientists and clinicians, she has successfully opened trials of genetically modified T cells in multiple myeloma, leukemia, mesothelioma, pancreatic and ovarian cancers, as well as glioblastoma multiforme.
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 University of Pennsylvania and in hematology and medical oncology at Memorial Sloan Kettering and is board-certified in these three disciplines.
Mark Leick, MD
Mark Leick, MD 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.
Rationale of Disease
CD70 as a target in AML. The inventors developed a CAR-T cell therapy to target this checkpoint inhibitor.
Azacitidine augments CD70-CAR potency by increasing antigen expression.
Acute myeloid leukemia (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 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.
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 treatment.
AML was uniformly fatal half a century ago, intensive chemotherapy now cures forty percent (40%) of adults. This is a substantial improvement, but there remains a significant unmet clinical need for older and relapsed and refractory patients where below ten percent (10%) of patients are cured. AML represents a unique burden because it affects various ages, involves extensive time in the hospital, is associated with high rates of infection and complications, and required the need for stem cell transplants (bone marrow).
Many AML patients are not eligible for intensive chemotherapy and there is an unmet need for more effective and less toxic treatments that improve the quality of life from the disease. AML patients also have a high rate of relapse, so treatments that reduce relapse are in high demand.
 Dong Y, Shi O, Zeng Q, et al. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. Published online June 19, 2020. doi:10.1186/s40164-020-00170-6
Background and Proof of Concept
The use of a CD70-targeting chimeric antigen receptor (CAR)-T cell to target liquid cancers, specifically AML, has not been seen before. Though the invention utilizes an existing strategy, this strategy has only been used in solid tumors, not liquid. Attempts to utilize adoptive cell therapy against CD70 were first reported in 2011 when investigators at NCI designed a CAR-T cell using CD70 ligand CD27 to target CD70 tumor cells. Based on these results, a clinical trial with this construct was launched in 2016 for patients with solid tumors expressing CD70, though results have not yet been reported (NCT02830724). AML was not an evaluated target in either of these studies. This invention covers the treatment of AML with this CD27-expressing CAR as it represents a novel avenue for CAR treatment. Using in vitro and in vivo mouse models, the inventors found CD70 targeted CAR-T cells are effective at eliminating models of AML and that AZA is effective at upregulating the CD70 protein and therefore treating AML
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.
This form of CAR T cell therapy for AML is completely novel that no companies are pursuing, leaving a gap in the market for this invention. This therapy uses a unique plasmid from the Maus Lab. This therapy offers a less toxic treatment for AML. Treatment for AML has changed little over the fifty years since the introduction of cytotoxic chemotherapy for the treatment of AML.
Novelty and Value Proposition
This is a completely novel CAR T cell treatment for AML. The use of CD70-directed CAR T cells has not been documented elsewhere. Targeting 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 $976.2B 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 11.0% from 2018 to 2023.
Leick, Mark, et al. "Use of CD70 targeted chimeric antigen receptor (CAR) T cells for the treatment of acute myeloid leukemia (AML)." Blood 134 (2019): 4443. https://doi.org/10.1182/blood-2019-127154
U.S. provisional 62/900,826
PCT/US2020/051018 (nationalized in U.S., Europe)