Abstract
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N ¼ 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57–18.35; P ¼ 0.007 and HR 6.91; 95% CI, 1.37–34.97; P ¼ 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non–small cell lung cancer (N ¼ 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1214-1225 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 79 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jan 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Dynamics of tumor and immune responses during immune checkpoint blockade in non–small cell lung cancer. / Anagnostou, Valsamo; Forde, Patrick M.; White, James R.; Niknafs, Noushin; Hruban, Carolyn; Naidoo, Jarushka; Marrone, Kristen; Ashok Sivakumar, I. K.; Bruhm, Daniel C.; Rosner, Samuel; Phallen, Jillian; Leal, Alessandro; Adleff, Vilmos; Smith, Kellie N.; Cottrell, Tricia R.; Rhymee, Lamia; Palsgrove, Doreen N.; Hann, Christine L.; Levy, Benjamin; Feliciano, Josephine; Georgiades, Christos; Verde, Franco; Illei, Peter; Li, Qing Kay; Gabrielson, Edward; Brock, Malcolm V.; Isbell, James M.; Sauter, Jennifer L.; Taube, Janis; Scharpf, Robert B.; Karchin, Rachel; Pardoll, Drew M.; Chaft, Jamie E.; Hellmann, Matthew D.; Brahmer, Julie R.; Velculescu, Victor E.
In: Cancer Research, Vol. 79, No. 6, 01.01.2019, p. 1214-1225.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dynamics of tumor and immune responses during immune checkpoint blockade in non–small cell lung cancer
AU - Anagnostou, Valsamo
AU - Forde, Patrick M.
AU - White, James R.
AU - Niknafs, Noushin
AU - Hruban, Carolyn
AU - Naidoo, Jarushka
AU - Marrone, Kristen
AU - Ashok Sivakumar, I. K.
AU - Bruhm, Daniel C.
AU - Rosner, Samuel
AU - Phallen, Jillian
AU - Leal, Alessandro
AU - Adleff, Vilmos
AU - Smith, Kellie N.
AU - Cottrell, Tricia R.
AU - Rhymee, Lamia
AU - Palsgrove, Doreen N.
AU - Hann, Christine L.
AU - Levy, Benjamin
AU - Feliciano, Josephine
AU - Georgiades, Christos
AU - Verde, Franco
AU - Illei, Peter
AU - Li, Qing Kay
AU - Gabrielson, Edward
AU - Brock, Malcolm V.
AU - Isbell, James M.
AU - Sauter, Jennifer L.
AU - Taube, Janis
AU - Scharpf, Robert B.
AU - Karchin, Rachel
AU - Pardoll, Drew M.
AU - Chaft, Jamie E.
AU - Hellmann, Matthew D.
AU - Brahmer, Julie R.
AU - Velculescu, Victor E.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N ¼ 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57–18.35; P ¼ 0.007 and HR 6.91; 95% CI, 1.37–34.97; P ¼ 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non–small cell lung cancer (N ¼ 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
AB - Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N ¼ 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57–18.35; P ¼ 0.007 and HR 6.91; 95% CI, 1.37–34.97; P ¼ 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non–small cell lung cancer (N ¼ 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
UR - http://www.scopus.com/inward/record.url?scp=85062974749&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062974749&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-1127
DO - 10.1158/0008-5472.CAN-18-1127
M3 - Article
C2 - 30541742
AN - SCOPUS:85062974749
VL - 79
SP - 1214
EP - 1225
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 6
ER -