Abstract B96: Adaptive resistance to therapeutic PD-1:PD-L1 blockade is mediated by upregulation of the TIM-3 immune checkpoint
Authors: Akbay Esra A. , Koyama Shohei , Li Yvonne Y. , Herter-Sprie Grit S. , Buczkowski Kevin A. , Richards William G. , Gandhi Leena , Redig Amanda J. , Rodig Scott J. , Asahina Hajime , Jones Robert E. , Kulkarni Meghana M. , Fecci Peter E. , Johnson Bruce E. , Janne Pasi A. , Engelman Jeffrey A. , Gangadharan Sidharta P. , Costa Daniel B. , Freeman Gordon J. , Bueno Raphael , Hodi F. Stephen , Dranoff Glenn , Wong Kwok-Kin , Hammerman Peter S. 
Published: May 2016

Abstract
Introduction:
Programmed death 1 (PD-1): Programmed death ligand 1 (PD-L1) immune checkpoint blockade has been demonstrated to be efficacious in a number of cancer types, including melanoma, renal cell carcinoma, bladder cancer, hematologic malignancies and non-small cell lung cancer (NSCLC) and anti-PD-1 antibodies have recently been approved for use in the United States and Asia. Anti-PD-1 therapeutic antibodies function through binding to PD-1 on tumor-reactive T cells and inhibiting the PD-1:PD-L1 interaction, thereby reinvigorating the anti-tumor T cell response. Expression of PDL1 in tumor cells and infiltrating immune cells and PD-1 in T cells has been associated with responsiveness to blockade of this immune checkpoint; however, mechanisms of both de novo and adaptive resistance to therapy are unclear.
Methods:
We used two genetically engineered mouse models of lung adenocarcinomas corresponding to the two most common oncogene drivers in human lung adenocarcinoma, Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR. The EGFR and Kras models were treated with a therapeutic anti-PD-1 antibody until tumors demonstrated progression by MRI and evaluated immune profiles. To confirm the applicability of these findings in patients, we also analyzed immune cells from patients who showed an initial response to PD-1 blockade but developed progressive disease several months after the initiation of treatment.
Results:
We identified upregulation of Tim-3 checkpoint receptor on therapeutic antibody-bound T cells as a marker of treatment resistance in mouse tumors. To determine whether blockade of Tim-3 at the time of resistance might be therapeutically efficacious, we performed Tim-3 blocking treatment in these mice and demonstrated a clinical benefit. Specimens from the two patients who developed progressive disease after an initial response to anti-PD1 treatments also exhibited similar upregulation of TIM-3 on therapeutic antibody-bound T cells, further supporting TIM-3 as a marker of treatment resistance.
Conclusions:
TIM-3 is upregulated in anti-PD-1 antibody bound T cells at the time of tumor regrowth in both genetically engineered mouse models and non-small cell lung cancer patients who initially responded to PD-1 blocking treatment. Targeting TIM-3 could be a promising option to reinitiate tumor-reactive T cell activation in patients who have developed adaptive resistance to anti-PD-1 treatment.
Citation Format: Esra A. Akbay, Shohei Koyama, Yvonne Y. Li, Grit S. Herter-Sprie, Kevin A. Buczkowski, William G. Richards, Leena Gandhi, Amanda J. Redig, Scott J. Rodig, Hajime Asahina, Robert E. Jones, Meghana M. Kulkarni, Peter E. Fecci, Bruce E. Johnson, Pasi A. Janne, Jeffrey A. Engelman, Sidharta P. Gangadharan, Daniel B. Costa, Gordon J. Freeman, Raphael Bueno, F. Stephen Hodi, Glenn Dranoff, Kwok-Kin Wong, Peter S. Hammerman. Adaptive resistance to therapeutic PD-1:PD-L1 blockade is mediated by upregulation of the TIM-3 immune checkpoint. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B96.