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

144s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2508 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
From bench to bedside: The use of the li-Key technology to improve helper
peptides for clinical use in cancer vaccines. Presenting Author: Timothy J.
Vreeland, San Antonio Military Medical Center, Ft. Sam Houston, TX
Background: Work involving peptide vaccines has shown that peptides
containing MHC Class II epitopes, which elicit CD4� T cell responses, may
play a role in potentiating an immune response. The Ii-Key peptide (amino
acids 77-80 of the immune-regulatory Ii protein), when covalently linked to
an MHC Class II epitope, can induce conformational change in the epitope
binding groove, increasing CD4� T cell stimulation up to 250 fold. Here we
present an update of results from clinical trials evaluating this novel
technology in an adjuvant breast cancer vaccine targeting HER2/neu.
Methods: We reviewed our trials investigating AE37, a hybrid peptide
created by the addition of the Ii-Key peptide (LRMK) to AE36 (GVGSPYVS-
RLLGICL), an MHC Class II-binding peptide from the intracellular domain
of the HER2 protein. We have completed a phase I study and are currently
conducting a randomized phase II trial of the AE37 peptide � GM-CSF in
the adjuvant treatment of disease-free breast cancer patients with any level
of HER2 expression (IHC 1-3� or FISH�1.2). Results: Phase I data showed
the vaccine to be safe and effective in raising anti-HER2 immunity.
Importantly, even the cohort of patients given AE37 without GM-CSF
showed significant increases in both in vivo and in vitro immune responses.
To date, we have enrolled 201 patients to our phase II trial (Vaccine
(VG)�103, Control (CG)�98). Toxicity has been minimal (99% of local
and systemic toxicities grade �2). VG patients have shown significant
increases in both in vivo and in vitro responses to both AE36 and AE37,
with consistently stronger responses to the AE37 hybrid peptide than the
native AE36. With a median f/u of 22 months, Kaplan Meier projections
estimate recurrence rates of 10.3% in the VG compared to 18% in the CG;
a 43% risk reduction. Conclusions: The AE37 peptide vaccine appears to be
effective in eliciting a strong immune response and possibly preventing
breast cancer recurrence. These results provide an important proof of
concept and suggest that additional studies evaluating Ii-Key hybrid
peptide vaccines are warranted, whether in the field of immunotherapy or
more traditional vaccines.
2510 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and
clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with
solid tumors. Presenting Author: Scott S. Tykodi, Fred Hutchinson Cancer
Research Center, Seattle, WA
Background: Blocking the interaction between programmed death-1 (PD-
1), a co-inhibitory receptor expressed by activated T cells, and its ligand
PD-L1 may enhance T-cell function. Here we describe the safety and
activity from the first clinical study of BMS-936559 in patients (pts) with
advanced solid tumors, further validating the importance of the PD-1/
PD-L1 pathway as a target for cancer therapy. Methods: BMS-936559 was
given Q2 wk IV in a 6-wk cycle at doses of 0.3�10.0 mg/kg during dose
escalation and/or cohort expansion; pts could receive up to 16 cycles (48
doses). Results: As of August 1, 2011, 162 pts with melanoma (MEL,
n�53), non-small-cell lung (NSCLC, n�50), colorectal (n�18), renal cell
(RCC, n�17), ovarian (n�17), and pancreatic (n�7) cancer were treated.
Median therapy duration was 11 wks (max 99 wks). Common related
adverse events (rAEs; �5% pts) included fatigue, diarrhea, infusion
reaction, arthralgia, rash, and pruritus. The incidence of grade 3-4 rAEs
was 8.6%. AEs of special interest included hypothyroidism, hepatitis,
sarcoidosis, endophthalmitis, and myasthenia gravis; there were no drugrelated
deaths. Clinical activity was observed in MEL, RCC, and NSCLC.
Objective responses (ORs; RECIST 1.0) were observed in heavily pretreated
pts. ORs were durable; among 16 pts with ORs, 7 had responses lasting �1
yr. Two other pts had ongoing ORs with durations of 2.3 and 8.5 mo at data
lock. Several pts had prolonged stable disease. Some pts had a persistent
reduction in overall tumor burden in the presence of new lesions but were
not categorized as responders. In NSCLC, ORs were observed irrespective
of histology. Conclusions: BMS-936559 was active and generally well
tolerated in pts with NSCLC, RCC, and MEL. In conjunction with data from
anti-PD-1/BMS-936558 trials, this study concurrently validates the importance
of the PD-1/PD-L1 pathway for cancer immunotherapy and supports
further clinical development of anti-PD-1/PD-L1 directed therapy.
Dose
(mg/kg)
MEL RCC NSCLC
N a OR uPR b RR c (%) N a OR uPR b RR c (%) N a OR uPR b RR c (%)
1 18 1 1 11 0 - - - 11 0 0 0
3 17 5 1 35 0 - - - 13 1 0 8
10 17 3 0 18 17 2 1 18 25 4 3 28
a response evaluable pts
b unconfirmed PR
c response rate ([OR � uPR] � N)
CRA2509 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors:
Clinical activity, safety, and a potential biomarker for response.
Presenting Author: Suzanne Louise Topalian, The Johns Hopkins University
School of Medicine, Baltimore, MD
The full, final text of this abstract will be available at
abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2,
2012, and in the Annual Meeting Proceedings online
supplement to the June 20, 2012, issue of Journal of
Clinical Oncology. Onsite at the Meeting, this abstract will
be printed in the Saturday edition of ASCO Daily News.
2511 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
Costimulatory effect of agonistic 4-1BB antibody on proliferation and
effector phenotype of tumor-infiltrating lymphocytes in melanoma. Presenting
Author: Amod Sarnaik, H. Lee Moffitt Cancer Canter & Research
Institute, Tampa, FL
Background: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL)
is a promising form of immunotherapy with a 20-30% durable response
rate. Its widespread implementation is limited by the relatively long time
needed to establish TIL in vitro and the lack of effective tumor reactivity.
Our objective was to incorporate co-stimulation with 4-1BB agonism to
optimize TIL growth preparation time and tumor reactivity to improve
outcomes. Methods: 7 metastatic melanoma patients were consented to an
IRB-approved tissue procurement protocol. For each specimen, TIL were
propagated in vitro from 4 melanoma tumor fragments per condition with
standard 6000 IU/mL of IL-2 and either 10 ug/mL of 4-1BB agonistic
antibody (BMS-663513) or its isotype control. After 3 weeks, TIL were
counted and phenotyped using flow cytometry. TIL were re-stimulated with
HLA-matched melanomas and assessed for interferon-� (IFN�) release by
ELISA. Statistical comparisons involved the 2-tailed, paired t test using
GraphPad Prism software. Results: 4-1BB treatment yielded a median
4.3x10 7 TIL (range 1.1x10 7 -8.4x10 7 ) compared to a median 2.3x10 7
cells in the control (range 1.5x10 6 -5.3x10 7 ,p� 0.009). This is clinically
significant as the initial minimum target number for TIL generation is
3x10 7 . On phenotypic analysis compared to control, 4-1BB treatment
resulted in a 1.5X higher CD8 � cell numbers (p�0.02), a 6X lower CD4 �
cell numbers (p�0.02), and 5.5X lower CD4 � CD25 � FoxP3 � Treg cell
numbers (p�0.09). A paired sample was re-stimulated in triplicate with
HLA-matched tumor target, and ELISA of the supernatant treated with
4-1BB yielded 1.6 fold higher IFN� (p�0.05). A paired sample was then
assayed for known markers of T cell cytolytic activity: EOMES and perforin.
4-1BB treatment resulted in 34.5% EOMES and perforin double positive
TIL compared to 18.8% in the control group. Conclusions: 4-1BB agonism
is associated with enhanced kinetics of TIL proliferation, increased yield of
CD8 � TIL, lower Treg numbers, increased markers of cytolysis, and
enhanced IFN� release upon tumor re-stimulation. 4-1BB agonism may be
a useful adjuvant in the generation of TIL in future clinical trials.
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