Researchers have verified a much-needed new target for treating cancers that often become resistant to existing therapies and become deadly.
In an early-phase clinical trial, the researchers tested a drug designed to target a protein called ROR1 and found convincing evidence of antitumor activity and no unexpected toxicities in 32 people with a variety of lymphoid cancers. The ROR1 targeted therapy shrank tumors fully or partially in 60% of subjects with one type of cancer and 47% with another type, providing the first clinical proof for selective targeting of ROR1 as a new approach to cancer therapy.
“The numbers are small, but this is quite promising,” said Stephen Spurgeon, M.D., senior author of the study, published online in NEJM Evidence. “This lays the foundation for a novel cancer therapy target for a patient population that is truly in need, without a lot of other options.” Spurgeon is an associate professor of medicine in the OHSU School of Medicine and director of the Lymphoma Program in the Knight Cancer Institute.
ROR1 is a protein that appears on the surface of cells during fetal development, where it relays signals that spur embryonic stem cells to multiply. By birth, ROR1 disappears from almost all normal tissues. But in cancer cells, the ROR1 gene can re-activate and start expressing the cell-surface protein. ROR1-expressing blood cancers and solid tumors appear to be more aggressive, resistant to treatment, and lethal.
The idea to target ROR1 began over a decade ago in the laboratory of Thomas Kipps, M.D., Ph.D., a professor of medicine at the UC San Diego Moores Cancer Center. His lab developed a monoclonal antibody that locks on to ROR1 with high specificity and safely, without causing too many off-target effects.
In the new study, the researchers combined the monoclonal antibody with a type of drug that blocks cell growth by stopping cell division. The antibody-drug conjugate – called Zilovertamab vedotin, or ZV – binds selectively to tumor cells expressing ROR1, where it releases the toxic drug. The researchers administered ZV intravenously to the 32 subjects in repeated three-week cycles until cancer progression or unacceptable toxicity.
Fifteen subjects had mantle cell lymphoma, seven had chronic lymphocytic leukemia and five had diffuse large B-cell lymphoma. Three had follicular lymphoma, one had marginal zone lymphoma, and one had Richter transformation lymphoma. All of the cancers were progressing despite a median of four prior treatments with anti-cancer drugs or cell therapies.
The ROR1 targeted therapy shrank tumors fully or partially in 7 of the 15 patients with mantle cell lymphoma (47%; 4 partial and 3 complete) and in 3 of 5 patients with diffuse large B-cell lymphoma (60%; 1 partial and 2 complete). The treatment induced regressions in several patients who had received extensive prior therapy, including high-dose chemotherapy with stem cell transplantation or CAR-T cell therapy
Many of the tumor regressions were long lasting. Treatment responses persisted 10 or more months in 7 of 10 patients whose tumors shrank. “Participating in this study definitely provided benefits to some of our patients that they otherwise would not have had access to,” Spurgeon said.
“It was no easy feat to conduct this phase 1 study with a novel agent amid a pandemic that severely strained every hospital,” Spurgeon said. “It’s a testament to the excellent team of coordinators, MDs, and RNs at the OHSU Knight Cancer Institute that allowed us to do this.”
Important questions remain unanswered. The researchers don’t know why no tumor responses were observed with chronic lymphocytic leukemia and other tumor types in the clinical trial. ROR1 is almost always expressed in chronic lymphocytic leukemia cancer cells. Spurgeon said the antibody-drug conjugate might not be delivering enough of the toxic agent into those cancers, or the cancers might have ways of resisting that particular agent.
Going forward, Spurgeon said other types of cancer-fighting drugs could be combined with the antibody to see which might optimize its impact. He said a number of clinical trials are taking shape to test ROR1-targeted therapy in cancers beyond lymphomas.
Meanwhile, he said, the present study continues to enroll lymphoma patients at OHSU and other clinical trial sites.
“It’s huge, to be able to provide these therapies locally,” Spurgeon said. “Our philosophy is that anyone can give standard of care treatment. It’s really on us to develop new therapies. We view ourselves as the last line of defense for our patients.”
Zilovertamab vedotin targeting of ROR1 as therapy for lymphoid cancers by Michael L. Wang and others. NEJM Evidence (Oct. 12, 2021)