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Clinical response and pathway-specific correlates following TIGIT-LAG3 blockade in myeloma: the MyCheckpoint
Shambavi Richard1, Alexander M Lesokhin2, Barry Paul3
1Tisch Cancer Institute, Icahn School of Medicine, New York, NY, USA.
Abstract:
Persons with myeloma were randomized to receive an anti-TIGIT (T cell immunoreceptor) or anti-LAG3 (lymphocyte activation gene) antibody followed by combination with pomalidomide and dexamethasone ( NCT04150965 ). Primary and secondary endpoints were safety and efficacy, respectively. Therapy was well tolerated without dose-limiting toxicity. Durable clinical responses were observed in both the anti-TIGIT(three of six participants) and the anti-LAG3 (two of six participants) arms. Anti-LAG3 responders had higher naive cluster of differentiation 4 (CD4)-positive T cells and lower programmed cell death protein 1-positive effector T cells. Anti-TIGIT responders had higher CD226 expression, natural killer cell activation and lower CD112 expression. These data demonstrate the clinical activity of TIGIT-LAG3 blockade and identify pathway-specific response correlates in myeloma.
Insights
This study shows that blocking T cell immunoreceptor (TIGIT) and lymphocyte activation gene 3 (LAG3) pathways with antibodies, combined with standard myeloma drugs, is safe and effective. Durable responses were seen, with specific immune cell markers predicting success in multiple myeloma patients.
Area of Science:
- Immunotherapy
- Oncology
- Hematology
Background:
- Multiple myeloma is a hematologic malignancy with limited treatment options.
- Immune checkpoint inhibitors targeting T cell immunoreceptor (TIGIT) and lymphocyte activation gene 3 (LAG3) are emerging as potential therapies.
- Understanding response correlates is crucial for optimizing TIGIT and LAG3 blockade in myeloma.
Purpose of the Study:
- To evaluate the safety and efficacy of combining anti-TIGIT or anti-LAG3 antibodies with pomalidomide and dexamethasone in patients with multiple myeloma.
- To identify biomarkers associated with clinical response to TIGIT-LAG3 blockade.
Main Methods:
- A randomized clinical trial (NCT04150965) involving patients with myeloma.
- Participants received either an anti-TIGIT or anti-LAG3 antibody in combination with pomalidomide and dexamethasone.
- Safety and efficacy were assessed as primary and secondary endpoints, respectively, with correlative immune cell analyses performed.
Main Results:
- The combination therapy was well tolerated, with no dose-limiting toxicities observed.
- Durable clinical responses were achieved in both the anti-TIGIT (3/6) and anti-LAG3 (2/6) arms.
- Specific immune profiles, including CD4+ T cell counts, PD-1+ T cells, CD226 expression, NK cell activation, and CD112 expression, correlated with response.
Conclusions:
- TIGIT-LAG3 blockade in combination with pomalidomide and dexamethasone demonstrates clinical activity in multiple myeloma.
- The study identifies pathway-specific immune correlates that can predict response to this novel immunotherapy approach.
- These findings support further investigation of TIGIT-LAG3 blockade for treating multiple myeloma.
