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Clinical trial for safety and tolerability of a neo-antigen cancer vaccine using antigen-presenting cells (Clinical trial of a neo-antigen cancer vaccine using antigen-presenting cells)

Neo-antigen cancer vaccination using antigen-presenting cells (Neo-antigen cancer vaccination)

Kawahara Norio

Aug. 31, 2024

3

Patient: Cancer & Sarcoma 1. Age at the time of informed consent: 20 to 75 years old 2. Performance status: 0/1 3. Pathological diagnosis as a type of cancer or sarcoma 4. Adjuvant therapy during the course of standard therapies 5. Already determined neo-antigens (Genetic mutation) under the cancer genomic diagnosis 6. Neither cardiovascular diseases nor respiratory disorders that would prevent blood apheresis 7. No organ function abnormalities, no blood abnormalities, no bleeding tendency 8. No infectious diseases 9. Understand the risk and benefit of the dendritic cell-vaccination 10. No other clinical trials

Of the five enrolled cases, two completed protocol treatment (six doses of neoantigen cancer vaccine) and one completed four doses. One other patient made a vaccine but did not administer it, and the other did not produce it.

No special notes

As a safety study, the safety was evaluated according to CTCAE v4.0. Of the five patients who consented, 2 completed 1 course, 1 withdrew during administration, 1 patient stopped the trial without administration after the neoantigen cancer vaccine was produced, and 1 patient was discontinued because the vaccine could not be produced due to apheresis difficulties. From the availability of raw materials through apheresis, the production and quality of individual neoantigen cancer vaccines were provided without any problems. The neoantigen cancer vaccine was well tolerated in advanced and recurrent cancers that were refractory to standard therapy, and safety was confirmed, and no adverse events were observed during the follow-up period. In terms of survival, which is a secondary endpoint, survival was confirmed for the two patients who completed treatment at 6 months and 1 year after the end of treatment, but survival was not reached until 2 years after the end of treatment. QOL was maintained with no adverse reactions to vaccine treatment. The immune response for the secondary endpoint was validated by an ELISpot assay using a personalized cancer antigen candidate peptide. In addition, the inductivity of immunity was verified from the viewpoint of immune memory. Samples were used before and after one course for two successful cases, Case 2 (NEO-002) and Case 3 (NEO-003), and after three doses in Case 5 (NEO-005). In Case 2, an immune response to the KRASWT (wild type) peptide conforming to HLA-A*33:03 (HLA class I) was detected after one course. In addition, an immune response corresponding to KRASWT peptides and KRASG12D peptides compatible with HLA-DRB1*07:01 and HLA-DRB1*09:01 (HLA class II) was detected. These immune responses were attenuated 6 months after termination. In Case 3 (NEO-003), an immune response to SMAD4WT peptides conforming to HLA-A*31:01 (Class I) was strongly detected after 3 and 6 doses. Immune responses were detected to SMAD4G365D peptides conforming to HLA-DRB1*04:01, HLA class II, and KRASG12D or WT peptides conforming to HLA-DRB1*09:01. Similarly, the immune response decreased 6 months after termination. In Case 5 (NEO-005), no immunoinducement against HLA class II-compliant TP53E258K, KRASWT or G12D peptide was detected after three doses. For the induction of immune memory by neoantigen cancer vaccines, the proportion of cancer antigen candidate peptide-specific CD8+ T cell memory subsets was analyzed. Case 2 (NEO-002), which tested positive for the ELISpot assay, showed an increase in CD8+ T effector memory T cells (TEM) after six doses. However, a significant decrease in TEM was observed 6 months after termination. NEO-002 showed no difference in the expression of CD137, an activation marker by KRASWT peptide stimulation, but patient 3 (NEO-003) observed an increase in TEM after one course and activation by SMAD4WT peptide stimulation (increase in CD137-positive CD8+ T cells).

A phase I study of a neoantigen-based vaccine was conducted. Of the five patients enrolled, three were administered to confirm the safety and tolerability of the neoantigen vaccine, and two patients who completed one course confirmed an immune response to the neoantigen peptide. This clinical trial first validated the feasibility and immunoinduceability of a personalized cancer vaccine that was expected to exhibit additional anti-tumor activity with optimized combination therapy.

Nov. 22, 2024

July. 14, 2023

https://www.mdpi.com/2072-6694/15/14/3627

https://jrct.mhlw.go.jp/latest-detail/jRCTc040210109

Shimodaira Shigetaka

Kanazawa Medical University

1-1 Daigaku, Uchinada, Kahoku, Ishikawa

shimodai@kanazawa-med.ac.jp

Yoshida Kenichi

Kanazawa Medical University hospital

1-1 Daigaku, Uchinada, Kahoku, Ishikawa

+81-76-218-8200

krmc@kanazawa-med.ac.jp

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Age at the time of informed consent: 20 to 75 years old
2. Performance status: 0/1
3. Pathological diagnosis as a tyep of cancer or sarcoma
4. Adjuvant therapy during the course of standard therapies
5. Already determined neo-antigens (Genetic mutation) under the cancer genomic diagnosis
6. Neither cardiovascular diseases nor respiratory disorders that would prevent blood apheresis
7. No organ function abnormalities, no blood abnormalities, no bleeding tendency
8. No infectious diseases
9. Understand the risk and benefit of the dendritic cell-vaccination
10. No other clinical trials

1. Application of molecular target medicine based on cancer genomic diagnosis
2. Allergy to penicillin or OK-432
3. Advanced diseases such as obstructive jaundice and involvement either in pleura or in peritoneum
4. Requiring platelet or red blood cell transfusion or albumin infusion
5. Disseminated intravascular coagulation syndrome and deep vein thrombosis
6. An infectious disease such as viral hepatitis (following the standard of the Japanese Red Cross Blood Center)
7. History of cerebrovascular disorders such as cerebral hemorrhage and infarction
8. Poor control of lung diseases such as chronic obstructive lung disease, bronchial asthma, and requiring oxygen dosage
9. Pneumonitis (the past)
10. Autoimmune diseases (present or the past)
11. Steroid hormone therapy continuously administered for diseases other than the prevention of temporal chemotherapeutic drug allergy
12. Mental disease (including neurosis, the panic disorder)
13. The past of epilepsy having poor control
14. Difficulty in arm vessel blood access for apheresis
15. No informed consent due to cancer
16. Inability to understand the risk and benefit of the DC vaccination
17. Pregnant or nursing women, desire to bear children
18. Under the treatment with immune checkpoint inhibitors during this clinical trial
19. Under the radiotherapy during this clinical trial
20. Physician judgment that a patient is inappropriate for treatment

Both

Cancer, sarcoma

D014611

Neo-antigen, cancer, antigen-presenting cell, vaccine

Cancer vaccination

D000230, D012509

Cancer, sarcoma

Safety (adverse reactions, severe adverse events)

1. One- and two-years survival ratio
2. Overall survival rate
3. Progression free survival at the 1 and 2 years
4. Antitumor effect (RECIST)
5. DTH (delayed type hypersensitivity reaction)
6. Immune monitoring of the biomarkers
(ELISpot assays, T cell markers)
7. QOL
8. Biomarker Search

Complete

+81-76-286-3511

Nov. 18, 2021