Abstract # 1152P

Phase 1 study of HSP105-derived peptide vaccine for patients with advanced esophageal cancer/ colo-rectal cancer. (EPOC1411)
S. Wada1, T. Kojima2, T. Nakatsura3, H. Bando2, O. Motohashi4, M. Shimomura3, T. Yoshikawa3, K. Kohashi5, A. Hori1, H. Ono6, M. Fukutani6, M. Wakabayashi6, S. Nomura6, A. Sato6, T. Sasada1, A. Ohtsu2
1) Cancer Immunotherapy, Kanagawa Cancer Center, 2) Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 3) Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center , National Cancer Center,4) Gastroenterology, Kanagawa Cancer Center, 5) Anatomic Pathology, Kyushu University, Fukuoka, 6) Clinical Research Support Office, National Cancer Center Hospital EastBackground

The HSP105 protein has been identified in pancreatic cancer by theSEREX method, and this protein has also been reported to play a rolein controlling apoptosis in cancer cells.
HSP105 is highly expressed in various human cancers, includingcolorectal cancer, esophageal cancer, pharyngeal cancer, pancreaticcancer, breast cancer, and melanoma.
We have therefore identified the respective HSP105-derived peptides
that bind to HLA-A24 and HLA-A2 (EP1536006, JP5112615,JP5291641, US9,404,925).
We investigated the safety and efficacy of HSP105-derived peptide
vaccine for patients (pts) with advanced esophageal cancer (EC) /colo‐rectal cancer (CRC).

Key Inclusion CriteriaHistologically confirmed advanced or metastatic squamous cell
carcinoma of the esophagus or adenocarcinoma of colon or rectum.
Refractory or intolerant to standard chemotherapy.
ECOG PS 0-1, age > 20, with measurable lesion (RECIST v1.1)
Adequate organ and bone marrow function
Positive one either or more of HLA-A*24:02, 02:01, 02:06 , 02:07.

HSP105-derived peptide vaccine is administered weekly byintradermal injection, for a maximum of 1 year.

Primary endpoint:P1a: Proportion of dose limiting toxicity , P1b: Response rate
Secondary endpoint:Progression free survival, Treatment failure rate, Adverse events
Immunological effects
Statistical consideration:
The recommended dose is determined based on the incidence ofdose limiting toxicity (DLT) during phase 1a (P1a).

Pts will then be added in phase 1b (P1b) to investigate the safety andefficacy of the vaccine.
HLA-A24 group
HLA-A*24:02

HLA-A2 group
HLA-A*02:01, A*02:06, A*02:07

Level 1
Level 0Level 1
Level 0Administered Vaccine
HSP105 A24-1
HSP105 A24-7
HSP105 A24-1
HSP105 A24-7
HSP105 A2-7
HSP105 A2-12
HSP105 A2-7
HSP105 A2-12

Dosage
3 mg
3 mg
1 mg
1 mg
3 mg
3 mg
1 mg
1 mg

Figure 2. Progression-free survival (N=30)

Figure 4. Establishment of HSP105 peptide-specific CTL clones

HLA-A24 group

Pt. 0009

HLA-A2 grouptarget30 pts enrolled in HSP-105 study

15 pts enrolled in HLA-A2 group※1

15 Discontinued protocol treatment
11 Progressive disease by RECIST
2 Clinical progression
2 patient refusal

15 Discontinued protocol treatment
14 Progressive disease by RECIST
1 Clinical progression

15 Intent-to-treat efficacy analysis
3 Included in the DLT assessment
15 Safety analysis

15 Intent-to-treat efficacy analysis
3 Included in the DLT assessment
15 Safety analysis

Esophageal

0.9 months(0.7 – 2.8 months)

Esophageal

1.0 months(0.7 – 1.9 months)

Colorectal

1.9 months(0.7 – 3.0 months)

Colorectal

1.6 months(0.6 – 3.0 months)

Table 1. Patients Characteristics (N=30)

GenderPrevious Radiotherapy

No. of prior regimens

CRC (N=7)EC (N=9)

CRC (N=6)

7166
6253
1
704224361
6
161
1
600
16726954541814403350.56060060123

Table 2. Treatment related Adverse Events (N=30)
HLA-A24 groupCD8HSP105 A2-7 specific CTL clone

HSP105 A24-1 specific CTL clone
IFN-ɤ ELISPOTT2A24-HSP105
A2-7

HepG2SW620

HLA-A*02:01/24:02

HLA-A*02:01/24:02

HSP105-

T2A24-HIV

HSP105+

T2A24-HSP105
A24-1

HepG2SW620

HLA-A*02:01/24:02

HLA-A*02:01/24:02

HSP105-

HSP105+

HLA-A2 group

EC (N=8)
MaleFemale
Median01
Yes
NoYes
No123>4

CD8

T2A24-HIV

Figure 3. Waterfall plot (N=30)

0.21%

0.089%

IFN-ɤ ELISPOT※1 Includes patients positive for either A*02:01, A*02:06 or A*02:07, and positive for HLA-A*24:02

HLA-A24 group0.062%

HSP105 A24-1
Single-Dextramer cell sort

HIV-Dextramer

Single0.029%HLA-A*24:02

PBMCs after in vitro stimulation

T2-HSP105 A2-7 cell sort

T2-HIV

15 pts enrolled in HLA-A24 group

Pt. 0021

HLA-A*02:01

Tumor infiltrating lymphocytes (TILs)

Figure 1. Patient flow diagram (N=30)

Previous Surgery

Endpoints and Statistical Considerations

Level



A total 30 pts (HLA-A24 group 15pts, HLA-A02 group 15 pts)
were enrolled and grouped into level 1.
No DLT occurred and no major safety problems werereported throughout the trial.

Age (years)
Performance
StatusStudy Treatment and Assessment


DextramerMethods and Results

CD107aContact e-mail: st-wada@hotmail.com

HLA-A2 group

HLA-A24 group(n=13)

HLA-A2 group(n=15)

Summary of the results*Two patients who had no data of tumor
diameter after the baseline.

Table 3. Overall Response (N=30)
HLA-A24 group

HLA-A2 group

N%

N%

Complete Response (CR)0000Partial Response (PR)0000

Stable Disease (SD)

426.7

320.0

Progressive Disease (PD)960.0

1280.013.300

A total 30 pts (HLA-A24 group 15pts, HLA-A2 group 15 pts) wereenrolled and grouped into level 1 which received intradermallyadministration of peptide vaccine (emulsifying agent: Montanide ISA51 VG) 3 mg/body.
No DLT occurred and no major safety problems were reported
throughout the trial. Although pts with objective clinical efficacy was
not apparent, 7 pts (HLA-A24 of 4 and HLA-A2 of 3) showed stabledisease 2 months after initiation of treatment.
The HSP105-derived peptide vaccine induced HSP105-specific CTL
response in 15 pts (50%) of 30 pts (HLA-A24 of 7 and HLA-A2 of 8).
Additionally, we established several HSP105 peptide-specific CTL
clones from PBMCs and tumor of pts vaccinated with HSP105 peptide
by single cell sorting using Dextramer or anti-CD107a antibody.

Any grade
N (%)

Grade 3/4
N (%)

Any grade
N (%)

Grade 3/4
N (%)

Cough

1 (6.7)0 (0.0)0 (0.0)0 (0.0)Not Evaluated (NE)

2Injection site reaction

13 (86.7)

0 (0.0)6 (40.0)0 (0.0)DCR (95% CI)

26.7 (7.8 to 55.1)

20.0 (4.3 to 48.1)

Malaise1 (6.7)0 (0.0)1 (6.7)0 (0.0)RR (95% CI)

0.0 (0.0 to 21.8)

0.0 (0.0 to 21.8)

Nausea1 (6.7)0 (0.0)0 (0.0)0 (0.0)

Table 4. Immunological Response (N=30)

Although objective clinical efficacy was not apparent,
HSP105‐derived peptide vaccine appears safe and well tolerated
with minimal local toxicity.

Pneumonitis

1 (6.7)0 (0.0)0 (0.0)0 (0.0)

HLA-A2 group

Clinical trial information:UMIN000017809

Fever

2 (13.3)

1 (6.7)0 (0.0)0 (0.0)Rash maculo-papular

1 (6.7)0 (0.0)0 (0.0)0 (0.0)No treatment-related deaths were observed.

HLA-A24 group
HSP105 specific CTL response

N%

N%

7

46.7

853.3

Conclusions


EPOC1411 study is an investigator-initiated IND clinical trials.
Research grant were provided by Japan Agency for Medical
Research and Development (AMED).