The promising alliance of anti-cancer electrochemotherapy with immunotherapy

Calvet, C.; Mir, Lluis M.

doi:10.1007/s10555-016-9615-3

Cited by 110 publications

(99 citation statements)

References 83 publications

(116 reference statements)

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“…Interestingly preliminary data sustain the use of ECT in association with systemic immune checkpoint inhibitors, such as anticytotoxic T lymphocyte-associated antigen-4 or antiprogrammed cell death protein 1 antibodies. The combined concept of local therapy with systemic immune checkpoint inhibition is currently being studied in prospective clinical trials and has the potential to further improve the success of cancer immunotherapy 35,36…”

Section: Resultsmentioning

confidence: 99%

Electrochemotherapy induces apoptotic death in melanoma metastases: a histologic and immunohistochemical investigation

Bigi¹,

Galdo²,

Cesinaro³

et al. 2016

CCID

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BackgroundElectrochemotherapy (ECT) is increasingly used in the treatment of primary and secondary skin tumors, but little is known about the pathologic mechanism responsible for tumor cell destruction in humans. Knowledge of detailed mechanism of host response after ECT may improve the treatment efficacy related to patient selection and technique refinements.AimThe aim of the study was to investigate the histopathology and mechanism of cell death after ECT in cutaneous melanoma metastases.MethodsSkin biopsy specimens were sequentially obtained after ECT of cutaneous melanoma metastases, during a follow-up period of 2 months. Results from histologic evaluation and immunohistochemical characterization of the inflammatory infiltrate (CD3, CD4, CD8, CD56, Granzyme-B) were compared with a panel of apoptosis-related markers.Main outcome measuresEvidence of the mechanism of tumor cell damage, identification of histological and immunohistochemical signs of apoptosis and/or necrosis underlining a possible time course of tumor destruction and inflammatory reaction after ECT.ResultsEarly signs of epidermal degeneration, an increase of the inflammatory infiltrate, and initial tumor cell morphological changes were already detected 10 min after ECT. The cell damage progression, as demonstrated by histological and immunohistochemical evidence using apoptotic markers (TUNEL and caspase-3 staining), reached a climax 3 days after treatment, to continue until 10 days after. Scarring fibrosis and complete absence of tumor cells were observed in the late biopsy specimens. A rich inflammatory infiltrate with a prevalence of T-cytotoxic CD3/CD8-positive cells was detected 3 h after ECT and was still appreciable 3 months later.ConclusionThis study attempts to define the time course and characteristics of tumor response to ECT. The observations suggest both a direct necrotic cell damage and a rapid activation of apoptotic mechanisms that occur in the early phases of the cutaneous reaction to ECT. A persistent immune response of T-cytotoxic lymphocytes could possibly explain the long-term local tumor control.

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Section: Resultsmentioning

confidence: 99%

Electrochemotherapy induces apoptotic death in melanoma metastases: a histologic and immunohistochemical investigation

Bigi¹,

Galdo²,

Cesinaro³

et al. 2016

CCID

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“…As an alternative, the efficacy of IL‐12 therapy could be enhanced by combining it with metronomic cyclophosphamide to selectively decrease the amount of Tregs, as IL‐12 effects are transient and induce a rebound in Tregs . Furthermore, immunotherapy generally has a more powerful effect in a minimal residual disease setting, thus, IL‐12 therapy could benefit from a combinatorial strategy with surgery or electrochemotherapy …”

Section: Discussionmentioning

confidence: 99%

Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer

Cicchelero

Denies

Haers

et al. 2016

Vet Comparative Oncology

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Interleukin 12 (IL-12) is a powerful immunostimulatory cytokine with a strong antitumoural activity. In this work, the immunological, anti-angiogenic and clinical effects of three consecutive intratumoural IL-12 electrogene therapy (EGT) treatments were evaluated in nine dogs with spontaneous cancer. In all the dogs, tumour biopsies and blood samples were taken prior, during and after the intratumoural IL-12 EGT (on days 1, 8, 35 and 1, 3, 8, 15, 35, respectively). An initial decrease in immune cells was followed by an increase above baseline 1-3 weeks after treatment initiation. Interestingly, the decrease in peripheral leukocytes 2 days after the first intratumoural IL-12 EGT coincided with erythema and tumour swelling. Transient increases of IL-12 and interferon γ were measured in the serum and the tumour tissue, whereas IL-10 transiently increased only in the serum. The effect of intratumoural IL-12 EGT on the levels of IL-24 and vascular endothelial growth factor in the sera and tumour biopsies differed per dog. Via contrast-enhanced ultrasound (US) (on days 1, 8 and 35), we demonstrated that intratumoural IL-12 EGT resulted in a significant decrease of the relative blood volume and blood flow speed in the tumour compared with baseline. Metastases were present in two dogs. In one of these dogs, IL-12 EGT of the primary tumour caused a transient partial regression of the metastases, but not of the primary tumour. The second dog with metastases did not survive long enough to complete the entire treatment cycle. Despite encouraging immunostimulatory and anti-angiogenic effects after intratumoural IL-12 EGT, no clinically relevant outcomes were observed in this study, as persistent tumour regression could not be obtained. On the other hand, the laboratory and US results hold great promise for combinatorial strategies of intratumoural IL-12 EGT with conventional antitumour (immuno)therapies.

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“…The first randomized clinical trial in humans with cutaneous metastases treated with CaEP or ECT using bleomycin, showed similar results between both techniques [8]. However, seems that tumor cells are more sensitive to bleomycin than normal ones [2]. Thus, need to be conducted to better understand the complex mechanism behind the CaEP [3][4][5][6][7] A previous study compared the use of bleomycin with calcium compounds as calcium chloride and calcium glubionate [5].…”

Section: Discussionmentioning

confidence: 99%

Electrochemotherapy Associated with Calcium Electroporation in Metastatic Feline Cutaneous Malignant Melanoma

Anjos

Rodrigues

Silva

et al. 2019

Acta Scientiae. Vet.

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Background: Calcium electroporation (CaEP) is a novel therapeutic treatment that has been studied for cancer due to its selective killing cancer cells by necrosis and danger signals. Besides that, electrochemotherapy (ECT) is an effective local treatment that involves the administration of chemotherapeutic drugs followed by delivery of electrical pulses to the tumor. The combination with ECT and CaEP has been reported in literature suggesting that additional response of immune system could have been enhanced by electroporation with calcium. This case, report on the successful treatment with CaEP combined with ECT for treatment of a regional metastasis in a feline model of malignant melanoma. Case: A 9-year-old, mixed breed cat was referred to the veterinary clinic with a 2-month history of cutaneous peripalpebral plaque lesion (0.19 cm³) and a submandibular lymph node enlargement (0.5 cm³). Incisional biopsy of the cutaneous lesion and fine-needle aspiration of submandibular lymph node confirmed a cutaneous melanoma with submandibular lymph node metastasis. Tumor staging was set in T1N1M0 according to WHO staging criteria. ECT for the primary lesion and lymph node metastasis was proposed. For the ECT, bleomycin (15,000 UI/m²) application was performed intravenous followed by electroporation (8 pulses of 100 μs at 1000 V/cm, and 1 Hz) using a needle array electrode consisted of two parallel rows with six needles in each row. At 28-day post-ECT complete remission of the primary tumor and metastatic foci was achieved. However, 120 days after ECT, recurrence was observed in submandibular and retropharyngeal lymph nodes. A second ECT approach was performed adding to bleomycin the intra lymph nodal application of calcium gluconate. The dose of calcium gluconate was diluted in an isotonic 0.9% NaCl solution resulting in a low concentration at 9 mM, injected in both metastatic lymph nodes (submandibular total volume: 1.4 ml; retropharyngeal total volume: 0.5 mL) and pulses were delivered immediately after drug administration. No systemic adverse effects were observed. Local adverse effects were considered mild as transitory edema and ulceration post procedure. One-week post-ECT+CaEP, complete remission of local metastasis occurred. However, the patient achieved five months disease free interval, and died during a surgical approach, achieving nine months of survival time. Discussion: Feline cutaneous malignant melanoma is an aggressive disease with a short survival time for the patients with mean of 4.5 months. CaEP is a novel anticancer treatment that has been study in the past years due to its selective killing cancer cells by necrosis and danger signals. The CaEP induces supraphysiological calcium influx into neoplastic cells leading to acute ATP depletion and necrosis of tumor cells. This use could be an interesting therapeutic choice for both human and veterinary medicine. In this patient, it was demonstrated a good clinical response with its use, showing temporarily tumor remission from the case presented with disea...

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The promising alliance of anti-cancer electrochemotherapy with immunotherapy

Cited by 110 publications

References 83 publications

Electrochemotherapy induces apoptotic death in melanoma metastases: a histologic and immunohistochemical investigation

Electrochemotherapy induces apoptotic death in melanoma metastases: a histologic and immunohistochemical investigation

Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer

Electrochemotherapy Associated with Calcium Electroporation in Metastatic Feline Cutaneous Malignant Melanoma

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