Predictors of ACT response

Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy using Expanded
Autologous Tumor-infiltrating Lymphocytes in Metastatic Melanoma Patients
Chantale Bernatchez1, Rahmatu Mansaray3, Orenthial J. Fulbright3, Christopher Toth3, Renjith
Ramachandran3, Seth Wardell3, Minying Zhang1, Jessica Chacon1, Richard Wu1, Priscilla Miller1, Sandy
Mahoney1, Gladys Alvarado1, Michelle Glass1, Peter Thall2, Patricia Fox2, Roland Bassett2, John D.
McMannis3, Elizabeth Shpall3, Victor Prieto4, Nicholas Papadopoulos1, Kevin Kim1, Jade Homsi1, Agop

Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy using Expanded
Autologous Tumor-infiltrating Lymphocytes in Metastatic Melanoma Patients
Chantale Bernatchez1, Rahmatu Mansaray3, Orenthial J. Fulbright3, Christopher Toth3, Renjith
Ramachandran3, Seth Wardell3, Minying Zhang1, Jessica Chacon1, Richard Wu1, Priscilla Miller1, Sandy
Mahoney1, Gladys Alvarado1, Michelle Glass1, Peter Thall2, Patricia Fox2, Roland Bassett2, John D.
McMannis3, Elizabeth Shpall3, Victor Prieto4, Nicholas Papadopoulos1, Kevin Kim1, Jade Homsi1, Agop
Bedikian1, Wen-Jen Hwu1, Sapna Patel1, Merrick I. Ross5, Jeffrey E. Lee5, Jeffrey E. Gershenwald5,
Anthony Lucci5, Richard Royal5, Janice Cormier5, Gregory Lizee1 Patrick Hwu1,* and Laszlo G.
Radvanyi1,*
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising
treatment for metastatic melanoma that is unresponsive to conventional therapies. Here, we report on
the results of a Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma
patients. Transiently lymphodepleted patients received their expanded TIL followed by two cycles of
high-dose (HD) IL-2 therapy. Altogether, 31 patients were treated with expanded TIL ranging from 8-
150 billion cells. Overall, 15/31 (48.4%) patients had an objective clinical response with one patient
having a complete response. The responses have been durable, with relapse-free survival of >10
months for the majority (10/15) of the responding patients and all responding patients being alive one
year after TIL ACT. Factors associated with objective tumor regression included a higher number of
TIL infused, a higher proportion of CD8+ TIL in the infusion product (P=0.0011), a more differentiated
effector phenotype of the CD8+ population and, unexpectedly, a higher frequency of CD8+ TIL coexpressing
the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA) (P=0.0006).
Tumor regression was also associated with the persistence of dominant TIL TCR Vβ clonotypes in vivo
for at least 3 months. No significant difference in telomere lengths of TIL between responders versus
non-responders was evident. These results indicate that immunotherapy with expanded autologous
TIL is capable of achieving high durable clinical responses in metastatic melanoma patients and that
CD8+ T cells, particularly differentiated effectors and cells expressing BTLA+, may be critical in
mediating tumor regression.