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Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients

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Abstract

Thymidylate synthase (TS) poly-epitope peptide (TSPP) is a 27-mer peptide vaccine containing the amino acidic sequences of three epitopes with HLA-A2.1-binding motifs of TS, an enzyme overexpressed in cancer cells, which plays a crucial role in DNA repair and replication. Based on the results of preclinical studies, we designed a phase Ib trial (TSPP/VAC1) to investigate, in a dose escalation setting, the safety and the biological activity of TSPP vaccination alone (arm A) or in combination with GM-CSF and IL-2 (arm B) in cancer patients. Twenty-one pretreated metastatic cancer patients, with a good performance status (ECOG ≤ 1) and no severe organ failure or immunological disease, were enrolled in the study (12 in arm A, nine in arm B) between April 2011 and January 2012, with a median follow-up of 28 months. TSPP resulted safe, and its maximal tolerated dose was not achieved. No grade 4 toxicity was observed. The most common adverse events were grade 2 dermatological reactions to the vaccine injection, cough, rhinitis, fever, poly-arthralgia, gastro-enteric symptoms and, to a lesser extent, moderate hypertension and hypothyroidism. We detected a significant rise in auto-antibodies and TS-epitope-specific CTL precursors. Furthermore, TSPP showed antitumor activity in this group of pretreated patients; indeed, we recorded one partial response and seven disease stabilizations (SD) in arm A, and three SD in arm B. Taken together, our findings provide the framework for the evaluation of the TSPP anti-tumor activity in further disease-oriented clinical trials.

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Abbreviations

5-FU:

5-fluorouracil

ANA:

Antinuclear antibodies

ANCA:

Anti-neutrophil cytoplasmic antibodies

APC:

Antigen-presenting cell

ASMA:

Anti-smooth muscle antibodies

CEA:

Carcinoembryonic antigen

CRP:

C-reactive protein

CTL:

Cytotoxic T lymphocyte

DC:

Dendritic cell

DMSO:

Dimethyl sulfoxide

ECOG:

Eastern Cooperative Oncology Group

ELISA:

Enzyme-linked immune absorbance assay

ELISPOT:

Enzyme-linked immunospot assay

ENA:

Extractable nuclear antigen antibodies

ESR:

Erythrocyte sedimentation rate

FACS:

Fluorescence-activated cell sorting

GCP:

Good clinical practice

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

GMP:

Good manufacturing practice

IVS:

In vitro stimulation

LDH:

Lactate dehydrogenase

mAb:

Monoclonal antibody

MEBD:

Most effective biological dose

MPX:

Myeloperoxidase

MTD:

Maximal tolerated dose

NK:

Natural killer

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PBMCs:

Peripheral blood mononuclear cells

PD:

Progressive disease

PFS:

Progression-free survival

PHA:

Phytohemagglutinin

PR:

Partial response

QoL:

Quality of life

RECIST:

Response evaluation criteria in solid tumors

RSV:

Respiratory syncytial virus

SD:

Stable disease

TAA:

Tumor-associated antigens

Tcm :

Central memory T cell

Tem :

Effector memory T cell

Treg :

Regulatory T cell

TS:

Thymidylate synthase

TSPP:

Thymidylate synthase poly-epitope peptide

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Acknowledgments

This study was supported by grants from the Italian Ministry of Scientific and Technological Research [MURST ex 40 %], the Ministry of Health (Bando Ricerca Finalizzata N° RF-2010-231355), and the “Associazione Culturale Federico II di Siena”, Italy. We wish to thank the head of the nurse team, Dr. Guido Fruscoloni; our distinguished nurse specialists Marco Bianchi, Erika Bindi, Nicola Cicatelli and Laura Spito, and the medical staff who offered the best care and management to the trial patients. Finally, we wish to thank all the patients and families who participated to the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All patients gave their informed consent prior to be enrolled in the study.

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    Authors and Affiliations

    1. Department of Medical Biotechnologies, Siena University, Siena, Italy

      Maria Grazia Cusi & Claudia Gandolfo

    2. Department of Experimental and Clinical Medicine, Catanzaro “Magna Graecia” University and Medical Oncology Unit, Catanzaro, Italy

      Cirino Botta, Pierfrancesco Tassone & Pierosandro Tagliaferri

    3. Unit of Radiotherapy, Department of Medical, Surgical Sciences and Neurosciences, Siena University, Viale Bracci 11, 53100, Siena, Italy

      Pierpaolo Pastina, Elodia Claudia Martino, Luigi Pirtoli & Pierpaolo Correale

    4. Unit of Pharmacy, Siena University Hospital, Siena, Italy

      Maria Grazia Rossetti

    5. Department of Biotechnology, Chemistry and Pharmacy, Siena University, Siena, Italy

      Elena Dreassi

    6. Unit of Rheumatology, Siena University Hospital, Siena, Italy

      Giacomo Maria Guidelli & Antonella Fioravanti

    7. Unit of Psychology, Siena University Hospital, Siena, Italy

      Marco Pagliuchi & Assunta Basile

    8. Unit of Radiology, Siena University Hospital, Siena, Italy

      Salvatore Francesco Carbone & Veronica Ricci

    9. Department of Medical, Surgical Sciences, Neurosciences Siena University, Siena, Italy

      Lucia Micheli

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    1. Maria Grazia Cusi
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    Correspondence to Cirino Botta or Pierpaolo Correale.

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    Maria Grazia Cusi and Cirino Botta have equally contributed to this work.

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    Cusi, M.G., Botta, C., Pastina, P. et al. Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients. Cancer Immunol Immunother 64, 1159–1173 (2015). https://doi.org/10.1007/s00262-015-1711-7

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