Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
A new drug that promotes natural immunity to specifically attack the lymphocytes of certain blood cancers, NVG-111, has a manageable safety profile with side effects typical of immunotherapies and preliminary evidence of efficacy.
Who Performed the Research and Where Was it Presented:
Dr. William Townsend from University College London Hospitals NHS Foundation Trust and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a protein that is expressed on the surface of certain blood cancers, including chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL). While it is present on cancer cells, it is not found on normal B cells, which makes it a potential target for new therapies. NVG-111 is a novel bispecific T-cell engager (BiTE), a.k.a. bispecific antibody that binds ROR1 and CD3. By binding to ROR1 on the cancer cell and CD3 on the T cell, NVG-111 brings these two cells in proximity to each other so that the T cell can destroy the cancer cell. Here, researchers reported on the long-term follow-up from a phase 1 clinical trial testing the safety of NVG-111 in humans.
Methods and Participants:
NVG-111 was administered as a continuous intravenous infusion at six different dose levels to patients with relapsed / refractory CLL and MCL. Patients received NVG-111 alone (N=5) or with ibrutinib (N=9).
Results:
- Fourteen patients enrolled in the study, including eleven with CLL and three with MCL, and half had received two prior therapies.
- 82% of patients with CLL had high-risk molecular features such as TP53 mutations.
- Patients received up to six 21-day cycles of treatment; half received at least 3 cycles..
- Common side effects included headache, nausea, and fatigue, which were mild to moderate in intensity.
- A little over half of patients (57%) experienced cytokine release syndrome (CRS), a known side effect of immunotherapies, which causes flu-like symptoms.
- 14% of patients experienced immune effector cell-associated neurotoxicity syndrome (ICANS), another known side effect of immunotherapies, which generally produces mental confusion symptoms.
- Three dose-limiting toxicities occurred, all of which were reversible.
- NVG-111 did not affect the normal lymphocytes, suggesting little or no effect on immunity to infections.
- Among twelve patients who could be evaluated for efficacy, 67% responded to treatment, and 33% had a complete response (although definitions were not provided).
- Of these twelve patients, about half did have disease progression over the two-year follow-up.
Conclusions:
An experimental drug using a novel immunotherapy approach to attack cancer cells in CLL / SLL had a manageable safety profile with side effects typical of immunotherapies and some preliminary evidence of efficacy. Researchers are now studying NVG-222, a next-generation BiTE, which was designed to have improved safety and a more convenient dosing schedule. A phase 1/2 clinical trial of NVG-222 for blood cancers is currently ongoing in the United Kingdom. Despite prior less encouraging studies of anti-ROR1 strategies, ROR1 is an exciting target due to its nearly exclusive presence on the cancerous B cells and not on normal cells. Hopefully, the BiTE mechanism will finally deliver on the therapeutic potential of such a specific target.
Links and Resources:
You can read the actual ASH abstract here: Encouraging long-term efficacy and safety from first-in-human phase 1 study of time-limited NVG-111 in relapsed/refractory CLL and MCL
Take care of yourself first.
Ann Liu, PhD
