The feasibility of using an autologous GM-CSF-secreting breast cancer vaccine to induce immunity in patients with stage II-III and metastatic breast cancers

Karen S Anderson, Timothy K Erick, Meixuan Chen, Heather Daley, Margaret Campbell, Yolonda Colson, Martin Mihm, Labib R Zakka, Marika Hopper, William Barry, Eric P Winer, Glenn Dranoff, Beth Overmoyer, Karen S Anderson, Timothy K Erick, Meixuan Chen, Heather Daley, Margaret Campbell, Yolonda Colson, Martin Mihm, Labib R Zakka, Marika Hopper, William Barry, Eric P Winer, Glenn Dranoff, Beth Overmoyer

Abstract

Purpose: The antigenic targets of immunity and the role of vaccination in breast cancer are unknown. We performed a phase I study of an autologous GM-CSF-secreting breast cancer vaccine in patients with metastatic and stage II-III breast cancer.

Methods: Tumor cells from patients with metastatic (n = 15) and stage II-III (n = 7) disease were transduced with a replication-defective adenoviral vector encoding GM-CSF, and then irradiated. Twelve and seven patients with metastatic and stage II-III disease, respectively, received weekly vaccination for three weeks, followed by every other week until disease progression or vaccine supply was exhausted (metastatic) or until six total vaccine doses were administered (stage II-III).

Results: Among those patients with metastatic disease who received vaccinations, eight had progressive disease at two months, three had stable disease for 4-13 months, and one has had no evidence of disease for 13 years. Of the patients with stage II-III disease, five died of metastatic disease between 1.16 and 8.49 years after the start of vaccinations (median 6.24 years) and two are alive as of September 2021. Toxicities included injection site reactions, fatigue, fever, upper respiratory symptoms, joint pain, nausea, and edema. Four of five evaluable patients with metastatic disease developed a skin reaction with immune cell infiltration after the fifth injection of unmodified, irradiated tumor cells.

Conclusion: We conclude that tumor cells can be harvested from patients with metastatic or stage II-III breast cancer to prepare autologous GM-CSF-secreting vaccines that induce coordinated immune responses with limited toxicity. TRIAL REGISTRATION AND DATE OF REGISTRATION: clinicaltrials.gov, NCT00317603 (April 25, 2006) and NCT00880464 (April 13, 2009).

Keywords: Autologous cellular vaccine; Breast cancer; GM-CSF.

Conflict of interest statement

GD is an employee of Novartis with stock ownership.

© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Figures

Fig. 1
Fig. 1
Vaccination induces local inflammation in patients with metastatic breast cancer. a GM-CSF-modified tumor cells were injected in contralateral limbs in patients with metastatic breast cancer. Skin site reactions were observed in seven patients 48–72 h after the first vaccine dose and in five patients after the fifth vaccine dose, and the longest dimension of erythema (cm) is shown, with patient numbers noted. Other patients did not exhibit any skin reaction. b Average baseline erythema at each vaccine dose level. c Unmodified cells at 106 cells/dose (DTH) were injected in contralateral limbs of seven patients with metastatic breast cancer. Skin site reactions were measured 48–72 h after the first and fifth injection. No responses were observed after the first injection. Four responses were observed after the fifth injection, and the longest dimension of erythema (cm) is shown, with patient numbers noted
Fig. 2
Fig. 2
Vaccination induces leukocyte infiltration. Representative skin biopsies from a patient with metastatic breast cancer showing inflammatory cellular infiltration following a injection of GVAX vaccine, and b following the fifth dose of 1 × 106 non-transduced, irradiated cells (DTH). Inflammatory infiltrate included lymphocytes, granulocytes, and macrophages
Fig. 3
Fig. 3
Immune profile for selected patients with metastatic breast cancer who received GVAX vaccine. a Immune profile among patients with stable disease or disease response following vaccination. b Immune profile among patients with disease progression following vaccination. Heatmaps of antibody response (normalized signal > 1.5) in vaccinated patients compared with healthy controls. D = Day number post-first GVAX vaccination

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