Japanease

Mar. 18, 2019

Mar. 31, 2020

jRCTs061180058

A phase I study of combination immunotherapy with HSP70 derived peptide, GPC3 derived peptide, IMP321 and Hiltonol for patients with advanced or metastatic solid cancer (A phase I study of combination immunotherapy with HSP70 derived peptide, GPC3 derived peptide, IMP321 and Hiltonol for patients with advanced or metastatic solid cancer)

YNP01 trial (YNP01 trial)

Mar. 26, 2019

17

Twenty-three patients were enrolled in our trial.Six of them were ineligible because of an HLA mismatch.A total of seventeen HLA-A*24:02-,02:01-,or 02:06-matched patients(six with CRC,five with EC,four with HCC,and one each with PDAC and Gastric cancer) comprised the study population and received vaccination therapy.Of these 17 patients,10 were male,median age was 64 years(range 41-78),16 patients were performance status(PS) 0 and one patient was PS1.The clinical stage was stage4 in 9 patients,4a in one,and 4b in 7,and 10 had recurrent tumor. 16 patients had previously received chemotherapy,and 14 patients had received operation.

Dose escalation was carried out in a three-patient cohort using 1 or 2 mg HSP70 and GPC3 combined with 250 or 1.000 mcg hLAG-3Ig/IMP321(Immutep S.A.,Chatenay Malabry,France) and 1.4 mg Poly-ICLC/Hiltonol(Oncovir,Inc.,Washington,DC,USA).Levels1/2 and level3 dosages of IMP321 were set as 250 mcg/injection and 1.000 mcg/injection,respectively.A fixed Hiltonol dosage of 1.4 mg/body was considered appropriate for vaccination therapy.The peptide/adjuvant mixtures were intradermally injected into four sites(bilateral thigh and axilla regions) on days 1,8,15,and 22 of each of two 28-d treatment courses.From the third treatment course onwards,the vaccinations were administered bi-weekly.By the fifth treatment course,the treatments were reduced to once every 4 weeks.Vaccination was continued after disease progression upon the requests of the patient and/or a primary physician.Dose-limiting toxicities(DLTs) were evaluated during the first treatment cycle(28d).Vaccines were well tolerated and there were no dose-limiting toxicities during dose escalation.In addition to the three scheduled cases,eight were added;in total,11 patients were enrolled at the recommended doses of 2.0 mg HSP70 and GPC3 together with 1.4 mg Poly-ICLC and 1.0 mg hLAG-3Ig.As a result,level3 dosage was considered appropriate for the clinical study.Of 17 patients received vaccination therapy,16 patients discontinued treatment due to cancer progression in 15 patients and patient request in 2 patients.

Severe adverse event were observed in 5 patients including, nausea, hypercalcemia, hypokalemia, ileus, small intestinal bleeding, pulmonary embolism, hyponatremia, ascites, pulmonary bleeding, bronchial stenosis, aspiration pneumoniae, appetite loss, upper respiratory tract infection, dyspnea, appendicitis, and ileus; however, there were no severe adverse events associated with vaccination therapy in any of the 17 patients at any dose. Adverse events associated with vaccination therapy were grade 1 injection site reactions (5/17, 29.4%) and grade 1 edema of the extremities (2/17, 11.7%).

Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11(64.7%) and 13(76.5%) cases,respectively.Specifically,HSP70-specific CTL inductions were observed in two of three patients at level1,one of three patients at level2,and 8 of 11 patients at level3 dosage.GPC3-specific CTL inductions were observed in two of three patients each at level1 and 2,and 9 of 11 patients at level3.HSP70-specific CTL induction was observed in 9 of 11 patients in HLA-A*24:02,one of five patients in HLA-A*02:01,and four of five patients in HLA-A*02:06.GPC3-specific CTL induction was observed in 9 of 11 patients in HLA-A*24:02 and three of five patients each in HLA-A*02:01 and HLA-A*02:06.Details of CTL induction are summarized in Table S2.Early and strong CTL induction was defined as a >= 3+ grade of peptide-specific spots after one course of vaccination therapy.Early,strong HSP70-specific and GPC3-specific CTL induction was observed in 54.5% and 45% of the patients at level3,respectively.In contrast,this response was observed in only one patient at levels 1 and 2 (P<0.05).To determine whether vaccination therapy re-invigorated exhausted T cells and improved the systemic immunosuppressive microenvironment, we analyzed surface marker expression in PBMCs before and after one course of treatment. In patients receiving level3 doses,the proportion of TIM3+ cells in the CD4+T cells significantly decreased(P=0.012) after one course of treatment in comparison with the pre-treatment condition(Fig. 3B and 3C).No significant changes were observed in the other cell surface markers before and after one course of treatment.Suppressive immune cell markers in PBMCs before vaccination were measured and the associations between these markers expression and OS were assessed.Patients were divided into high(>median) and low(<median) groups on the basis of median values of the proportions of surface marker expression.OS was then compared between pairs of groups.There was a significant association between PD-1 expression on the CD4+ T cells,TIM3 expression on the CD4+ T cells,and TIGIT expression on the CD8+ T cells and the OS(P=0.039,0.025 and 0.032,respectively).Moreover,there was a tendency of association between PD-1 expression on CD8+ T cells and the OS(P=0.058).The condition of patients remained stable for 2-34 months,and the DCR was 29%.The OS in CRC,HCC,and ESCC were 80%,75%,and 60% at 6 mo and 50%,75%,and 0% at 12 mo,respectively.This cancer vaccination therapy consisting of multi HLA binding HSP70/GPC3 peptides and hLAG 3Ig and Poly ICLC adjuvants was safe and effective for the rapid induction of a CTL response to HSP70/GPC3 proteins.

This phase I study evaluated the safety, peptide-specific CTL, and antitumor effects of a novel vaccination therapy comprising multi-HLA-binding HSP70/GPC3 peptides and adjuvants of LAG-3Ig and Poly-ICLC against gastrointestinal cancers. Seventeen patients received therapy without DLT. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 and 13 cases. Tumor markers were decreased in 10 cases. This novel peptide vaccination therapy was safe and effective for patients with GI cancer.

Mar. 31, 2020

No

none

https://jrct.niph.go.jp/latest-detail/jRCTs061180058

Nagano Hiroaki

Yamaguchi University Hospital

1-1-1,MinamiKogushi,Ube City

+81-836-22-2264

geka2dm@yamaguchi-u.ac.jp

Hazama Shoichi

Yamaguchi University School of Medicine

1-1-1,MinamiKogushi,Ube City

+81-836-22-2888

hazama@yamaguchi-u.ac.jp

Jan. 12, 2016

18

Interventional

single arm study

open(masking not used)

no treatment control

single assignment

treatment purpose

none

1.patients with advanced or metastatic solid cancer (Pancreatic cancer, colon cancer, gastric cancer, esophageal cancer, liver cancer and breast cancer) proven by histology or imaging (CT or MRI)
2. Patients with HLA-A*2402 -A*0201 -A*0206
3. Standard treatment failure cancer
4. Age; 20>=
5. Performance Status (PS); 0-1, Eastern Cooperative
Oncology Group (ECOG)
6. Preserved organ functions (number of WBCs more than
2.0x103/mm3; % of lymphocyte >=15; number of platelets
>=7.5x103/mm3; hemoglobin >=8.0 g/ dl; creatinine <=2.5
times of upper normal limit)
7.Patients provided written, informed consent to participate

The exclusion criteria were, double cancer, pneumonitis, severe allergy, severe infection, neurological disturbance, uncontrolled general diseases, heart diseases, general steroid treatment, or any prior therapies using same agents of this study.

20age old over
No limit

Both

patients with advanced or metastatic solid cancer

Combination Immunotherapy with peptide vaccination

safety

specific CTL response
Antitumor effect(OS PFS CR+PR CR+PR+SD)
Immune-related response criteria

Complete

NEC Corporation
Not applicable
CYTLIMIC Inc.
Not applicable
Yamaguchi University Certified Review Board
1-1-1,Minami Kogushi,Ube City, Yamaguchi

+81-836-22-2428

yrinsyo@yamaguchi-u.ac.jp
Approval

Mar. 06, 2019

UMIN000020440
UMIN Clinical Trials Registry(UMIN-CTR)