NEW YORK CITY—Dr. Myron Czuczman's presentation here at the Lymphoma & Myeloma International Congress on Hematologic Malignancies was titled “Novel Monoclonal Antibodies,” but he added “and Immunoconjugates” to be a more accurate description of this rapidly changing field.
One novel treatment he was enthused about in particular is inotuzumab ozogamicin (CMC-544), an antibody- targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. It is internalized and can be mixed with drugs, conjugates, toxins, or radioisotopes, said Dr. Czuczman, Professor and Chief of the Lymphoma/Myeloma Service and Head of the Lymphoma Translational Research Laboratory at Roswell Park Cancer Institute.
CMC-544 is an IgG4 antibody with no biological activity and is basically a delivery system.
“It does not induce antibody-dependent cell-mediated cytotoxicity or complement killing or signaling; it only delivers the payload of calicheamicin into the cell,” he said.
Dr. Czuczman cited preliminary data from a Phase I study of CMC-544, of which he is one of the investigators, showing a 44% objective response rate in 79 patients with diffuse large cell or follicular lymphoma. (Advani et al: JCO 2010;28: 2085-2093).
Patients with follicular lymphoma treated at the maximum tolerated dose had a 68% overall response rate and a median progression-free survival of 10.4 months.
But in diffuse large B-cell lymphoma, the objective response rate was only 15% at the maximum tolerated dose, and median progression-free survival was 49 days.
The major toxicity was reversible thrombocytopenia, occurring in 90% of patients treated at the maximum tolerated dose.
“Keep in mind that these agents are not benign, they do have side effects, and we do need to understand the mechanisms of action and resistance,” he said. “But if we can combine them logically they are very powerful tools in our hands.”
Thrombocytopenia was again a major toxicity (30%) in a Phase I/II trial of CMC-544 in combination with rituximab in patients with follicular lymphoma and large cell lymphoma reported at the 2009 ASH Annual Meeting (Abstract 584) by Nam H. Dang, MD, PhD, with Dr. Czuczman as a coauthor.
That trial so far has seen some very high response rates, he said. Follicular lymphoma patients had an 84% response rate, with a 60% complete response rate at more than one year. In patients with diffuse large B-cell lymphoma there is durable activity with an 80% objective response rate and 50% CR.
One MAB Good, Two May Be Better
The idea of dual antibody therapy—rituximab and CMC-544, for instance—intrigues Dr. Czuczman.
“With respect to low-risk FLIPI, you may not need to use a chemotherapy-based agent; rituximab alone is good, but maybe two antibodies theoretically would be better.
“And if you can get a delay with that low-risk patient, getting a good response of one, two, or three years, you may be delaying the onset of toxic chemotherapy for years.
Future Directions: Pretargeting Radioimmunotherapy
In a list of future directions, Dr. Czuczman included pretargeting radioimmunotherapy.
He said pretargeting involves two steps, rather than a single step of using a whole antibody combined with a radioisotope.
“First you get something that binds to the tumor cell such as a modified antibody. Anything in the circulation in excess—that is, that is not effective on the tumor cell—gets cleared out.
“Then comes the second part that actually has the payload—the radioisotope, for example—and that binds to the first part.”
This concentrates more of the binding antibody to the tumor cells, and when the second step is given it rapidly binds to just the tumor sites.
He said the biotechnology involved is getting to the point where he expects to see it used in clinical trials soon.