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Annual Meeting Proceedings Part 1 - American Society of Clinical ...

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144s Developmental Therapeutics—<strong>Clinical</strong> Pharmacology and Immunotherapy<br />

2508 Oral Abstract Session, Mon, 3:00 PM-6:00 PM<br />

From bench to bedside: The use <strong>of</strong> the li-Key technology to improve helper<br />

peptides for clinical use in cancer vaccines. Presenting Author: Timothy J.<br />

Vreeland, San Antonio Military Medical Center, Ft. Sam Houston, TX<br />

Background: Work involving peptide vaccines has shown that peptides<br />

containing MHC Class II epitopes, which elicit CD4� T cell responses, may<br />

play a role in potentiating an immune response. The Ii-Key peptide (amino<br />

acids 77-80 <strong>of</strong> the immune-regulatory Ii protein), when covalently linked to<br />

an MHC Class II epitope, can induce conformational change in the epitope<br />

binding groove, increasing CD4� T cell stimulation up to 250 fold. Here we<br />

present an update <strong>of</strong> results from clinical trials evaluating this novel<br />

technology in an adjuvant breast cancer vaccine targeting HER2/neu.<br />

Methods: We reviewed our trials investigating AE37, a hybrid peptide<br />

created by the addition <strong>of</strong> the Ii-Key peptide (LRMK) to AE36 (GVGSPYVS-<br />

RLLGICL), an MHC Class II-binding peptide from the intracellular domain<br />

<strong>of</strong> the HER2 protein. We have completed a phase I study and are currently<br />

conducting a randomized phase II trial <strong>of</strong> the AE37 peptide � GM-CSF in<br />

the adjuvant treatment <strong>of</strong> disease-free breast cancer patients with any level<br />

<strong>of</strong> HER2 expression (IHC 1-3� or FISH�1.2). Results: Phase I data showed<br />

the vaccine to be safe and effective in raising anti-HER2 immunity.<br />

Importantly, even the cohort <strong>of</strong> patients given AE37 without GM-CSF<br />

showed significant increases in both in vivo and in vitro immune responses.<br />

To date, we have enrolled 201 patients to our phase II trial (Vaccine<br />

(VG)�103, Control (CG)�98). Toxicity has been minimal (99% <strong>of</strong> local<br />

and systemic toxicities grade �2). VG patients have shown significant<br />

increases in both in vivo and in vitro responses to both AE36 and AE37,<br />

with consistently stronger responses to the AE37 hybrid peptide than the<br />

native AE36. With a median f/u <strong>of</strong> 22 months, Kaplan Meier projections<br />

estimate recurrence rates <strong>of</strong> 10.3% in the VG compared to 18% in the CG;<br />

a 43% risk reduction. Conclusions: The AE37 peptide vaccine appears to be<br />

effective in eliciting a strong immune response and possibly preventing<br />

breast cancer recurrence. These results provide an important pro<strong>of</strong> <strong>of</strong><br />

concept and suggest that additional studies evaluating Ii-Key hybrid<br />

peptide vaccines are warranted, whether in the field <strong>of</strong> immunotherapy or<br />

more traditional vaccines.<br />

2510 <strong>Clinical</strong> Science Symposium, Sat, 1:15 PM-2:45 PM<br />

PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and<br />

clinical activity <strong>of</strong> BMS-936559, an anti-PD-L1 antibody, in patients with<br />

solid tumors. Presenting Author: Scott S. Tykodi, Fred Hutchinson Cancer<br />

Research Center, Seattle, WA<br />

Background: Blocking the interaction between programmed death-1 (PD-<br />

1), a co-inhibitory receptor expressed by activated T cells, and its ligand<br />

PD-L1 may enhance T-cell function. Here we describe the safety and<br />

activity from the first clinical study <strong>of</strong> BMS-936559 in patients (pts) with<br />

advanced solid tumors, further validating the importance <strong>of</strong> the PD-1/<br />

PD-L1 pathway as a target for cancer therapy. Methods: BMS-936559 was<br />

given Q2 wk IV in a 6-wk cycle at doses <strong>of</strong> 0.3�10.0 mg/kg during dose<br />

escalation and/or cohort expansion; pts could receive up to 16 cycles (48<br />

doses). Results: As <strong>of</strong> August 1, 2011, 162 pts with melanoma (MEL,<br />

n�53), non-small-cell lung (NSCLC, n�50), colorectal (n�18), renal cell<br />

(RCC, n�17), ovarian (n�17), and pancreatic (n�7) cancer were treated.<br />

Median therapy duration was 11 wks (max 99 wks). Common related<br />

adverse events (rAEs; �5% pts) included fatigue, diarrhea, infusion<br />

reaction, arthralgia, rash, and pruritus. The incidence <strong>of</strong> grade 3-4 rAEs<br />

was 8.6%. AEs <strong>of</strong> special interest included hypothyroidism, hepatitis,<br />

sarcoidosis, endophthalmitis, and myasthenia gravis; there were no drugrelated<br />

deaths. <strong>Clinical</strong> activity was observed in MEL, RCC, and NSCLC.<br />

Objective responses (ORs; RECIST 1.0) were observed in heavily pretreated<br />

pts. ORs were durable; among 16 pts with ORs, 7 had responses lasting �1<br />

yr. Two other pts had ongoing ORs with durations <strong>of</strong> 2.3 and 8.5 mo at data<br />

lock. Several pts had prolonged stable disease. Some pts had a persistent<br />

reduction in overall tumor burden in the presence <strong>of</strong> new lesions but were<br />

not categorized as responders. In NSCLC, ORs were observed irrespective<br />

<strong>of</strong> histology. Conclusions: BMS-936559 was active and generally well<br />

tolerated in pts with NSCLC, RCC, and MEL. In conjunction with data from<br />

anti-PD-1/BMS-936558 trials, this study concurrently validates the importance<br />

<strong>of</strong> the PD-1/PD-L1 pathway for cancer immunotherapy and supports<br />

further clinical development <strong>of</strong> anti-PD-1/PD-L1 directed therapy.<br />

Dose<br />

(mg/kg)<br />

MEL RCC NSCLC<br />

N a OR uPR b RR c (%) N a OR uPR b RR c (%) N a OR uPR b RR c (%)<br />

1 18 1 1 11 0 - - - 11 0 0 0<br />

3 17 5 1 35 0 - - - 13 1 0 8<br />

10 17 3 0 18 17 2 1 18 25 4 3 28<br />

a response evaluable pts<br />

b unconfirmed PR<br />

c response rate ([OR � uPR] � N)<br />

CRA2509 <strong>Clinical</strong> Science Symposium, Sat, 1:15 PM-2:45 PM<br />

Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors:<br />

<strong>Clinical</strong> activity, safety, and a potential biomarker for response.<br />

Presenting Author: Suzanne Louise Topalian, The Johns Hopkins University<br />

School <strong>of</strong> Medicine, Baltimore, MD<br />

The full, final text <strong>of</strong> this abstract will be available at<br />

abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2,<br />

2012, and in the <strong>Annual</strong> <strong>Meeting</strong> <strong>Proceedings</strong> online<br />

supplement to the June 20, 2012, issue <strong>of</strong> Journal <strong>of</strong><br />

<strong>Clinical</strong> Oncology. Onsite at the <strong>Meeting</strong>, this abstract will<br />

be printed in the Saturday edition <strong>of</strong> ASCO Daily News.<br />

2511 <strong>Clinical</strong> Science Symposium, Sat, 1:15 PM-2:45 PM<br />

Costimulatory effect <strong>of</strong> agonistic 4-1BB antibody on proliferation and<br />

effector phenotype <strong>of</strong> tumor-infiltrating lymphocytes in melanoma. Presenting<br />

Author: Amod Sarnaik, H. Lee M<strong>of</strong>fitt Cancer Canter & Research<br />

Institute, Tampa, FL<br />

Background: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL)<br />

is a promising form <strong>of</strong> immunotherapy with a 20-30% durable response<br />

rate. Its widespread implementation is limited by the relatively long time<br />

needed to establish TIL in vitro and the lack <strong>of</strong> effective tumor reactivity.<br />

Our objective was to incorporate co-stimulation with 4-1BB agonism to<br />

optimize TIL growth preparation time and tumor reactivity to improve<br />

outcomes. Methods: 7 metastatic melanoma patients were consented to an<br />

IRB-approved tissue procurement protocol. For each specimen, TIL were<br />

propagated in vitro from 4 melanoma tumor fragments per condition with<br />

standard 6000 IU/mL <strong>of</strong> IL-2 and either 10 ug/mL <strong>of</strong> 4-1BB agonistic<br />

antibody (BMS-663513) or its isotype control. After 3 weeks, TIL were<br />

counted and phenotyped using flow cytometry. TIL were re-stimulated with<br />

HLA-matched melanomas and assessed for interferon-� (IFN�) release by<br />

ELISA. Statistical comparisons involved the 2-tailed, paired t test using<br />

GraphPad Prism s<strong>of</strong>tware. Results: 4-1BB treatment yielded a median<br />

4.3x10 7 TIL (range 1.1x10 7 -8.4x10 7 ) compared to a median 2.3x10 7<br />

cells in the control (range 1.5x10 6 -5.3x10 7 ,p� 0.009). This is clinically<br />

significant as the initial minimum target number for TIL generation is<br />

3x10 7 . On phenotypic analysis compared to control, 4-1BB treatment<br />

resulted in a 1.5X higher CD8 � cell numbers (p�0.02), a 6X lower CD4 �<br />

cell numbers (p�0.02), and 5.5X lower CD4 � CD25 � FoxP3 � Treg cell<br />

numbers (p�0.09). A paired sample was re-stimulated in triplicate with<br />

HLA-matched tumor target, and ELISA <strong>of</strong> the supernatant treated with<br />

4-1BB yielded 1.6 fold higher IFN� (p�0.05). A paired sample was then<br />

assayed for known markers <strong>of</strong> T cell cytolytic activity: EOMES and perforin.<br />

4-1BB treatment resulted in 34.5% EOMES and perforin double positive<br />

TIL compared to 18.8% in the control group. Conclusions: 4-1BB agonism<br />

is associated with enhanced kinetics <strong>of</strong> TIL proliferation, increased yield <strong>of</strong><br />

CD8 � TIL, lower Treg numbers, increased markers <strong>of</strong> cytolysis, and<br />

enhanced IFN� release upon tumor re-stimulation. 4-1BB agonism may be<br />

a useful adjuvant in the generation <strong>of</strong> TIL in future clinical trials.<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

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