The Sentinel

THE OFFICIAL BLOG OF THE SOCIETY FOR IMMUNOTHERAPY OF CANCER (SITC).

SITC 2017 Scientific Highlights - Nov. 10



The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the first day of the 32nd Annual Meeting in National Harbor, Md. (Scroll to the bottom of this blog post to view the Glossary)



Co-administration of novel anti-sMIC antibody increases anti-CTLA-4 therapeutic response in TRAMP/MIC mice (O22)

Jennifer Wu, PhD (Northwestern University, Chicago, IL) presented recently-published data investigating the efficacy of a novel antibody targeting the highly immunosuppressive human activation immune receptor natural killer group 2D (NKG2D) ligand, sMIC, with the goal of increasing anti-CTLA-4 therapeutic response. Using a TRAMP (transgenic adenocarcinoma of the mouse prostate)/MIC mouse model, Wu’s group found that mice with increased circulation of tumor-derived sMIC receiving anti-CTLA-4 had ~25% decrease in survival over 8 weeks compared to mice receiving placebo (p < 0.05), as well as an increased risk of immune-related colitis. TRAMP/MIC mice receiving anti-CTLA-4 in combination with anti-sMIC had reduced prostate tumor burden (~0.25g vs ~6g, respectively; p < 0.001), increased DC activation, enhanced TCR/CD3 signaling, and increased T cell clonality in tumor infiltrates compared to mice receiving anti-CTLA-4 alone (P < 0.05). CR was observed in 4/5 combination-treated mice for at least 120 days post-therapy, with no cases of immune-related colitis. These pre-clinical anti-sMIC/anti-CTLA-4 data align with clinical observations in patients with mCRPC, melanoma and multiple myeloma who have demonstrated improved responses to anti-CTLA-4 therapy if they develop sMIC autoantibodies during the course of treatment. These results suggest that sMIC may act as a predictive biomarker for anti-CTLA-4 response. Furthermore, including anti-sMIC antibodies in CTLA-4-targeted therapies may reduce irAES and increase treatment efficacy.

Anti-PD-1 agent nivolumab shows promise in solid tumor patients selected for treatment according to biomarker status (O37)

Nilofer Azad, MD (Johns Hopkins University, Baltimore, MD) discussed preliminary results from arm Z1D of the large NCI- MATCH (Molecular Analysis for Therapy Choice) trial investigating the efficacy of single or combination agents, selected according to the genetic profile of the tumor, in patients with advanced, refractory solid tumors, lymphoma or myeloma. In the Z1D arm, 35 patients with advanced non-colorectal dMMR-positive solid tumor or lymphoma received the anti-PD-1 agent nivolumab, 3 mg/kg IV Q2W for four 28-day cycles, then 480 mg IV Q4W. MMR deficiency was defined by complete loss of tumor staining for MLH1 or MSH2 by IHC. Preliminary data were collected from 34 patients (median age 60 yrs; 76% white; 68% female; 42% >3 prior therapies; 71% MLH1-, 29% MSH2-). ORR was 24% (95% CI: 11-41; 2 unconfirmed CR, 8 PR, 4 unconfirmed PR, 11 SD) with median DOR not yet reached (3.7 - 7.4+ mos, 7/8 remain on treatment). PFS at 6 months was 49% (95% CI: 32-67). Grade 3/4 TRAEs, most commonly anemia (n=7), occurred in 15/33 (46%) patients, and led to 7 (21%) treatment withdrawals. These data suggest that nivolumab has significant efficacy and expected tolerability in patients with dMMR biomarker-positive non-colorectal cancers. Future work will interrogate tumor tissue to assess T cell infiltration and define possible biomarkers of resistance to this type of immunotherapy.

Pembrolizumab does not impair viral suppression or CD4 cell count in patients with HIV and cancer receiving antiretroviral therapy (O40)

Thomas Uldrick, MD (National Cancer Institute, Bethesda, MD) presented data from the multicenter phase 1 CITN-12 study investigating the safety of pembrolizumab (200mg IV Q3W) in HIV-positive patients with advanced or refractory cancers receiving antiviral therapy. The data are intended to increase understanding of anti-PD-1 tolerability in the HIV-positive population, which has typically been excluded from trials of anti-PD-1/L1 agents due to immunosuppression. The study population, which was stratified by CD4+ cell count, had >4 weeks prior antiretroviral therapy (ART), HIV viral load <20 copies/mL, and no hepatitis B or C. Patients (n = 17, median age 56 yrs, 94% male, 76% white; median CD4+ cell count 249 cells/µL) maintained HIV viral load suppression throughout the study and, importantly, there was a trend towards increasing CD4+ cell counts over time, although this did not reach statistical significance. A total of 82 AEs (93% grade 1/2) potentially related to pembrolizumab were observed; incidence of grade 3/4 AEs (3 anemia, 1 increased ALT, 1 increased AST, 1 decreased neutrophil count) bore no relationship to CD4+ count. Immune-related AEs included subclinical hypothyroidism (n=6, 35%), pneumonitis (n=3, 12%), joint stiffness (n=1, 6%) and ALT elevation (n=2, 18%), all manageable with disease-specific treatment or corticosteroids. Of the 10 serious AEs, two were potentially attributable to pembrolizumab, including one patient with sarcomatoid lung cancer who developed hepatic metastasis as well as markedly raised liver enzymes that were treated effectively with steroids. In an additional case of interest, one patient with Kaposi sarcoma received pembrolizumab and ultimately died due to complications associated with Kaposi sarcoma herpesvirus (KSHV) dissemination. These preliminary results suggest that standard dose pembrolizumab is well-tolerated and does not compromise viral suppression in patients with cancer who are receiving effective ART for HIV, potentially creating an avenue for checkpoint inhibitor use in a previously excluded patient population

First-line combination nivolumab + ipilimumab leads to long-term survival in patients with advanced melanoma: pooled 3-year CheckMate data (O21)

F. Stephen Hodi, MD (Dana-Farber Cancer Institute, Boston, MA) presented 3-year pooled efficacy and safety data from patients randomized to nivolumab + ipilimumab (nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W x 4, followed by nivolumab 3 mg/kg Q2W) in the phase II CheckMate 069 and phase III CheckMate 067 studies, both in advanced melanoma. Of the 407 patients who received combination nivo/ipi (mean age 60 yrs; 66% male; 4% brain metastases; 44% stage M0/M1a/M1b, 56% stage M1c; 70% BRAF wild-type, 30% BRAF mutant; 26% PD-L1 ≥5%), after 3 years 30 (7.4%) remain on treatment (median duration 40 months) and 277 (93%) have discontinued treatment, primarily due to drug toxicity (44%) or disease progression (26%); there were 5 (1%) deaths. ORR in the 409 patients randomized to nivo/ipi was 58.4% (95%CI: 53.5-63.3; 82 CR, 157 PR, 50 SD, and 89 PD). Median reduction in tumor burden was 58%, and median duration of response was NR. At median follow-up of 37.5 months, median PFS was 12.4 months (95%CI: 9.6-21.9) and median OS was NR. After 3 years, 78% of nivo/ipi responders were alive and off study therapy (vs. 54% of nivo responders [HR = 0.4] and 32% of ipi responders [HR = 0.2]). Median DOR for nivo/ipi was NR and 69% of patients required no further treatment (versus 42% of nivo and 32% of ipi patients). Treatment-free interval (time from discontinuation of study therapy to starting subsequent therapy, including patients who had not started subsequent therapy) was 27, 11 and 3 months in nivo/ipi, nivo and ipi arms, respectively. In all, 41% of nivo/ipi patients required subsequent therapy (versus 56% and 72% of nivo and ipi patients). Almost all patients experienced TRAEs, predominantly diarrhea (45%), fatigue and pruritus (38%) and rash (33%); grade 3/4 events (58%) led to discontinuation in 30% of patients and there were 5 deaths (1.2%). In summary, first-line nivolumab + ipilimumab led to a longer treatment-free interval and higher rate of treatment-free survival than either nivolumab or ipilimumab alone.

First-line combination nivolumab + ipilimumab may become the new standard of care in patients with advanced/metastatic renal cell carcinoma (O38)

Robert Motzer, MD (Memorial Sloan Kettering Cancer Center, New York, NY) presented new OS subgroup data from the CheckMate 214 study investigating the efficacy of combination nivo/ipi in treatment-naïve patients with advanced or metastatic renal cell carcinoma (aRCC). Data presented at the ESMO 2017 annual congress revealed that combination nivo/ipi reduced the risk of death by 37% in patients with IMDC-defined intermediate/poor risk disease (n=425; median OS NR [95% CI: 28.2 – NR]) compared to patients who received standard of care sunitinib (n=422, median OS 26 months [95% CI 22.1 – NR]; hazard ratio 0.63 [99.8% CI, 0.44-0.89, p < 0.0001]). New data presented today at SITC 2017 expanded on these results with new subgroup analyses showing that OS was increased when patients received combination nivo/ipi compared to sunitinib regardless of age, sex, region, baseline IMDC, or prior nephrectomy. While OS was increased in the PD-L1 <1% cohort (n=562, HR = 0.73 [95% CI: 0.56-0.96], p=0.025), the OS advantage was even more marked in patients with PD-L1 ≥1% (n=214, HR = 0.45 [95% CI: 0.29-0.71], p < 0.001). ORR in the PD-L1<1% (p = 0.0252) and ≥1% (p < 0.0001) subgroups showed a similar trend. PFS was only increased compared to the sunitinib arm in patients with PD-L1 ≥1% (p = 0.0003). Whereas quality of life, measured using the functional assessment for cancer therapy – kidney symptom (FKSI)-19 index, decreased in sunitinib patients, it significantly improved from baseline in IMDC intermediate/poor-risk patients receiving nivo/ipi. These promising data support combination nivolumab + ipilimumab as first-line standard of care in patients with IMDC intermediate/poor-risk aRCC, with particular benefit in patients with PD-L1 ≥1%.

Targeting T cell mitochondrial metabolism enhances anti-PD-1 response in the pre-clinical setting


Greg Delgoffe, PhD (University of Pittsburgh, Pittsburgh, PA) discussed data assessing the impact of mitochondrial metabolism in TIL anti-tumor activity. Initial studies revealed that TILs from patients with head and neck cancer (p < 0.05) and melanoma (p ≤ 0.001) had reduced mitochondrial mass. This observation led Delgoffe’s group to investigate the role of the transcriptional co-activator PGC1α, which regulates mitochondrial biogenesis, in this phenotype. PGC1α was reduced ~10-fold in TILs compared to T cells in both draining and non-draining lymph nodes. To complement this defect, T cells overexpressing PGC1α were generated and introduced into B16ova mice, and this resulted in a 20% reduction in tumor area compared to mice receiving control T cells. To better understand PGC1α regulation in TILs, assessment of co-stimulatory molecules revealed increased 4-1BB expression in the most exhausted cells. 4-1BB expression increased OCR, a measure of metabolism, in TILs (p < 0.05), which inhibits TIL anti-tumor activity. As such, mice were administered anti-41BB and anti-PD1 in combination, or as monotherapy, to assess anti-tumor activity. Only mice receiving combination anti-PD-1/anti-4-1BB (4/9; 44%) were found to be tumor-free. Anti-tumor effects were consistent in mice who received only a 3 day short-course of anti-4-1BB therapy in conjunction with anti-PD-1 therapy. It was subsequently hypothesized that the type II diabetes drug metformin, which also inhibits mitochondrial OCR, in conjunction with anti-PD-1 therapy, would increase anti-tumor activity. This was found to be the case in 7/9 mice. These data suggest that suppression of TIL OCR can enhance anti-tumor activity and that targeting TIL metabolism in combination therapies may reduce development of immune checkpoint inhibitor resistance.
 

Glossary

AE = adverse event
CI = confidence interval
CR = complete response
DC = dendritic cell
dMMR = deficient DNA mismatch repair
DOR = duration of response
ECOG = Eastern Cooperative Oncology Group
G3/4 = grade 3 or 4
IHC = immunohistochemistry
IMDC = International Metastatic Renal Cell Carcinoma Database Consortium
irAE – immune-related adverse event
mCRPC = metastatic castration-resistant prostate cancer
MHC = major histocompatibility complex
NK = natural killer
NR = not reached
OS = overall survival
ORR = objective response rate
PD = progressive disease
PFS = progression-free survival
PR = partial response
Q2W = every 2 weeks
Q3W = every 3 weeks
SD = stable disease
TCR = T cell receptor
TRAE = treatment-related adverse event

No comments:

Post a Comment