Comparing Effect of CAR-T, ADC, and Double-Antibody for the Treatment of Hematological Tumors
Hematological tumors mainly include myeloma, leukemia (including ALL, CLL, AML, CML) and lymphoma (including HL and NHL). Each year, there are 30,000, 60,000 and 80,000 new patients respectively diagnosed with these three diseases in the United States. Because the blood tumor microenvironment is relatively simple and the B cell resistance is very strong, the blood tumor drug development is relatively easy, and there are many products on the market. The 5-year survival rates of the above three major hematologic tumors were 50%, 70%, and 90% respectively.
The CAR-T design technology targeted for CD19 and BCMA is the most mature, and now a great many of such projects are being researched. Since the CD19 was first confirmed and two products were already on the market, the introduction of new technologies may bring about more fruitful achievements. Among them, Sloan's so-called armed CAR-T design is complex, including an EGFR fragment as a brake mechanism (cleared with EGFR antibody), a CD28 signaling delivery domain in addition to CD3, and a 4-1BB ligand that activates non-CAR-T bystander T cells. This is called 1928z-41BBL (representing CD19, CD28, CD3, 41BBL, respectively) producing CR of 60% (NHL) and 78% (DLBCL) with good safety and no severe CRS. Unum's CAR-T is a CD16 that binds to an antibody Fc fragment and binds to any antibody, while the antibody is responsible for finding the target tumor cells. They published some biomarker data but no response data. ALLO's allogeneic CD19 CAR-T produces 82% CR and is also safe.
BCMA is also very popular. According to incomplete statistics, there are already about 10 companies and research institutes that have entered the clinical BMCA CAR-T. These treatments are very effective, and many still have nearly 100% response to patients, but persistence is a major question that needs to be further addressed. NK cell therapy and CD38 CAR-NK also showed good efficacy in people with CD38 antibody resistance.
Although CAR-T is extremely powerful in treating cancer, it is inconvenient to manufacture and use, and the price is high, and the safety control is difficult. Double-antibodies and ADCs targeting the same target are in the traditional drug category, showing sufficient efficacy for several known targets, including those for mAb-resistant patients. For example, the regenerative CD20-C3 double-antibody REGN1979 produced 100% response, 80% CR in R/R FL patients, and Roche's similar drug Mosunetuzumab also produced 38% CR in FL. Amgen's BCMA/CD3 double-antibody AMG420 shows 70% ORR, 40% CR, and a longer half-life AMG701 is under development.
Many new target drugs have shown promise in clinical trials at different stages. Karyopharm's small molecule XPO1 covalent inhibitor selinexor produces 30% ORR and 10% CR in patients with DLBCL who are resistant to multiple drugs. XPO1 is responsible for the transport of various proteins, including many tumor suppressor genes, from the nucleus to the cytoplasm. Argenix's CD70 antibody, Cusatuzumab, produced 92% of the ORR in the most refractory hematologic tumor AML, which was acquired by Johnson & Johnson for $500 million. Affimed’s CD30/CD16A Double Antibody, AFM13, produces 44% ORR in patients with CD30-positive lymphoma, and produces 88% ORR and 46% CR in HL when combined with Keytruda. TG Therapeutic's U2 combination of CD20 antibody ublituximab and PI3Kdeta inhibitor umbralisib, together with Keytruda, yields 90% ORR in CLL.
On December 5, 2018, the 60th Annual Meeting of the American Association of Hematology held in San Diego was closed. This is the world's largest blood disease academic conference, with a total of 25,000 participants who are all scientists from various countries. One of the biggest highlights at this annual meeting was Gilead's HPV-positive TCR solid tumor cell therapy Kite-439 (obviously from Kite acquisition), which produced 50% ORR in 12 HPV-positive epithelial cell carcinomas. This is a good sign, marking the early use of CAR-T in solid tumors.
Many patients die from hematological tumors each year, and the side effects of existing therapies need to be eradicated or lessened. Different killing mechanisms of the same antigen have different curative effects. The effect of CD19 and BCMA are limited. In contrast, CAR-T, double antibody and ADC are very effective. CAR-T is highly effective in patients with recurrent diseases. Although it is more important to find new targets that do not respond to existing target drugs, improving control of confirmed targets also has high value for drug-resistant populations.
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