17 maart 2021: Aanvullend op onderstaande informatie hier het volledige studierapport Low-dose cyclophosphamide selectively expands resident anti-tumor Tcells allowing in situ control of colorectal cancer in PDF formaat.

28 maart 2017 lees ook dit artikel:

https://kanker-actueel.nl/NL/immuuntherapie-geeft-uitstekende-resultaten-bij-darmkanker-met-minimale-ziekte-weinig-tumoren-en-zelfs-bij-darmkanker-stadium-iv-werkt-het-ook-al-is-het-dan-minder-effectief.html

28 maart 2017. Bron: ASCO-SITC (Society for Immunotherapy of Cancer) Clinical Immuno-Oncology Symposium

Immuuntherapie met een gemoduleerd virus, het zogeheten Ankara-ST4 virus, plus een lage dosis cyclophosphamide geeft uitstekende resultaten bij eerder met chemo voorbehandelde inoperabele darmkankerpatienten met vergevorderde darmkanker. Progressievrije ziektetijd ging van 2,4 naar 5 maanden en mediane overall overleving van 11,2 naar 20,0 maanden in de groep patiënten met de optimale behandeling.

Dit blijkt uit een kleinschalige open-label fase I/II veiligheidsstudie bij totaal 52 patienten met inoperabele darmkanker.

Bijna alle patiënten hadden eerder een chemokuur gehad met of capecitabine (Xeloda) en 5-FU (fluorouracil) en de meesten hadden daarna ook nog andere chemokuren of behandelingen gehad.

Werkingsmechanisme van het Ankara virus (TroVax)

Studie opzet:

Patiënten werden gerandomiseerd ingedeeld in geen behandeling (n = 8), of een lage dosis cyclophosphamide met 50 mg 2x daags gedurende behandelingsweken 1 en 3 (n = 9), of een vaccin met het gemoduleerde virus Ankara–5T4 only (n = 17), of lage dosis cyclophosphamide gevolgd door het gemoduleerde virus Ankara–5T4 (n = 18). Patiënten in de vaccingroep startten de behandeling op dag 22, nadat zij eerder cyclophosphamide hadden gekregen. Zij kregen 5 injecties om de 2 weken de 6e injectie 4 weken na de 5e injectie. Het primaire doel was te zien of de behandeling een boost te zien gaf in de anti-5T4 genen op dag 43 door het meten van gestegen T-cellen en/of antibody responses.

Kernpunten uit de studie:

A novel therapeutic vaccine employs a highly attenuated strain of vaccinia virus, modified vaccinia virus Ankara, and encodes the tumor antigen 5T4, which is found on 90% of colorectal cancers.
In a phase I/II trial of advanced colorectal cancer patients, modified vaccinia virus Ankara–5T4 plus low-dose cyclophosphamide (delivered prior to vaccination) led to robust immune responses that were associated with improved progression-free and overall survival.
Low-dose cyclophosphamide alone also produced strong immune responses that were associated with prolonged remission.

Een opmerkelijk citaat van de studieleider:

This is the first randomized study to show a clear benefit of immunotherapy in advanced colorectal cancer—and to suggest this approach may be superior to (and less toxic than) continuous palliative chemotherapy in these patients.

— Martin Scurr, PhD

Studie resultaten:

“Nadat we de cyclofosfamide gaven, zagen we dat de patiënten met de grootste vermindering van regulerende onderdrukkende T-cellen het meeste profiteerden met een progressievrije overleving,” aldus Dr. Scurr gemeld. “Gewoon het geven van een lage dosis cyclofosfamide alleen gaf ook al een immuunrespons te zien.”

Cyclophosphamide verzwakte regulerende onderdrukkende T cellen bij 21 van de 27 patiënten gedurende de eerste drie weken (P = .0028). Onder de 27 met cyclophosphamide behandelde patiënten, bereikten er 12 een vermindering van minimaal 39.4% (het doel dat statistisch significantie betekende). Deze verzwakking van de regulerende T-cellen werd ook gerelateerd aan een langere progressie vrije ziekte in de groepen die ook cyclophosphamide hadden gekregen, vergeleken met de groep patiënten die niet de 39,4% vermindering hadden gehaald. Mediane progressie vrije ziekte werd 5.0 vs 2.4 maanden voor deze groep van patiënten. (hazard ratio = 0.48, P = .09).

Een vaccinatie erbij verdubbelde de anti-5T4 immuun reacties bij 16 van de 35 patiënten welke waren behandeld met het gemoduleerde virus Ankara–5T4. Deze patiënten ervaarden een progressievrije ziekte van 5,6 maanden versus 2,4 maanden. (HR = 0.21, P = .0002) en een mediane overall overleving van 20.0 maanden vs 11.2 maanden; HR = 0.32, P = .0076).
Belangrijk te melden dat er geen extra ernstige bijwerkingen optraden bij deze aanpak.

In dit studie rapport, vrij in te zien: TroVax in colorectal cancer wordt beschreven hoe TROVAX werkt en gaat vergezeld van een interessante referentielijst. Zie ook hieronder. Interessant is ook dat Trovax bij ook andere vormen van kanker b.v. nierkanker, prostaatkanker wordt onderzocht en hoopvolle resultaten geeft.

Een andere studie van immuuntherapie met het gemoduleerde virus Ankara is deze review studie: 5T4-modified vaccinia Ankara: progress in tumor-associated antigen-based immunotherapy maar daarvoor moet worden betaald. En het abstract geeft te weinig informatie om daaruit conclusies op te kunnen maken.

Het studierapport: Scurr M, Pembroke T, Adams R et al: MVA-5T4 immunotherapy and low-dose cyclophosphamide for advanced colorectal cancer (TaCTiCC): An open-label, randomized phase I/II trial is nog niet vrij in te zien.

Hieronder wel het abstract na het abstract en referentielijst van de eerder genoemde studie: TroVax in colorectal cancer

The existing results support the ability of TroVax to induce immune responses within the host;

. 2014 Nov; 10(11): 3196–3200.

Published online 2014 Oct 31. doi: 10.4161/21645515.2014.973323

PMCID: PMC4514084

TroVax in colorectal cancer

Julie Rowe^1,^* and Putao Cen¹

Abstract

Currently, the backbone of therapy for metastatic disease is cytotoxic chemotherapy, along with the recent addition of targeted therapy based on molecular markers with KRAS testing. Despite the improvement in survival for metastatic colon cancer, newer agents are still needed. The clinical activity of TroVax in metastatic colon cancer has been studied in a small number of clinical trials. There is evidence that supports the vaccine's ability to induce humoral and cellular responses, as demonstrated by positive 5T4 and MVA-specific antibody titers and cellular proliferation assays. Future strategies should focus on investigating the immunomodulatory effects of chemotherapy in conjunction with TroVax, understanding the optimal dosing and schedule of the combination, and examining potential predictive biomarkers to determine which patients may benefit from immunotherapy from those who do not.

Abbreviations

ADCC: Antibody-dependent cell-mediated cytotoxicity
CEA: Carcinoembryonic antigen
CRC: Colorectal cancer
DT: Doubling time
EBNA-1: Epstein Barr-Virus nuclear antigen-1
EGFR: Epidermal growth factor receptor
HRPC: Hormone refractory prostate cancer
IHC: Immunohistochemoical
ITT: Intention to treat
LMP-2: Latent membrane protein-2 antigens
mCRC: Metastatic colon cancer
mRCC: Metastatic renal cell carcinoma
MSKCC: Memorial Sloan-Kettering Cancer Center
MVAs: Modified vaccinia Ankara
NSCLC: Non-small cell lung cancer
OS: Overall survival
PD-1: Programmed death 1 receptor
PD-L1: Programmed-death ligand 1
PFS: Progression free survival
PMNs: Peripheral blood mononuclear cells
RCC: Renal cell carcinoma
TAAs: Tumor-associated antigens
T-FOLFOX: Trovax and FOLFOX
T-FOLFIRI: Trovax and FOLFIRI
TILs: Tumor-infiltrating lymphocytes
TTP: Time to progression
VEGF: Vascular-endothelial growth factor; References

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Conclusions: Both CPM and TroVax induced highly beneficial anti-tumor immune responses resulting in significantly prolonged survival of end-stage CRC patients without toxicity. This is the first study to show a clear benefit of immunotherapy in advanced CRC, and suggests this approach may be superior (and less toxic) to continuous palliative chemotherapy in these patients.

MVA-5T4 immunotherapy and low-dose cyclophosphamide for advanced colorectal cancer (TaCTiCC): An open-label, randomized phase I/II trial.

Meeting:

2017 ASCO-SITC Clinical Immuno-Oncology Symposium

Category:

Therapies Targeting T cells

Subcategory:

Clinical Trials

Session Type and Session Title:

Poster Session A

Abstract Number:

154

Citation:

J Clin Oncol 35, 2017 (suppl 7S; abstract 154)

Author(s):

Martin Scurr, Tom Pembroke, Richard Adams, Daniel Blount, Alison Brewster, Sarah Gwynne, Richard Harrop, Robert Jones, Robert Hills, Awen Gallimore, Andrew Godkin; Cardiff University School of Medicine, Cardiff, United Kingdom; Velindre Cancer Centre, Cardiff, United Kingdom; Oxford Biomedica, Oxford, United Kingdom; South West Wales Cancer Centre, Swansea, United Kingdom

Background: Current immunotherapies including checkpoint inhibitors and vaccines for advanced colorectal cancer (CRC) have been largely ineffective. We hypothesized that combining an MVA-based vaccine targeting the tumor-associated antigen 5T4 (TroVax) with low-dose cyclophosphamide to deplete Foxp3⁺regulatory T-cells (Tregs), could improve immunological responses and patient outcomes.

Methods: In this open-label phase I/II clinical trial, TaCTiCC (TroVax and Cyclophosphamide Treatment in Colorectal Cancer) 53 patients with inoperable metastatic CRC were randomized to receive either no treatment (group 1, n=8), metronomic low-dose CPM (50mg B.D. during treatment weeks 1&3; group 2, n=9), TroVax only (6 i.m. injections weeks 4 to 16, group 3, n=18), or low-dose CPM followed by TroVax (group 4, n=18). The primary endpoint was boosted anti-5T4 responses at week 7, as measured by increased T-cell and antibody responses; secondary endpoints included progression-free (PFS)/overall survival (OS), and anti-5T4 responses over the trial period.

Results: CPM depleted Tregs in 21/27 patients during treatment week 3 (p=0.0045), resulting in significantly prolonged PFS amongst groups 2&4 over group 1 (5.0 vs. 2.5 months, HR=0.17 95% CI 0.048-0.62, p=0.0072). TroVax induced a >2-fold increase in anti-5T4 immune responses in 15/36 group 3&4 patients; these patients experienced significantly prolonged median PFS (6.5 vs. 2.4 months, HR 0.31 95% CI 0.14-0.65, p=0.0022) and OS (20 vs. 12 months, HR=0.37 95% CI 0.17-0.82, p=0.014). Combination of CPM & TroVax was not significantly superior. The primary endpoint at a single timepoint was not met since CPM-induced responses declined by week 7, and TroVax-induced responses were greatest at weeks 10-16. No serious adverse events were reported.

Conclusions: Both CPM and TroVax induced highly beneficial anti-tumor immune responses resulting in significantly prolonged survival of end-stage CRC patients without toxicity. This is the first study to show a clear benefit of immunotherapy in advanced CRC, and suggests this approach may be superior (and less toxic) to continuous palliative chemotherapy in these patients. Clinical trial information: 54669986.

darmkanker, chemo, xeloda - capecitabine, overall overleving, ziektevrije tijd, progressie vrije tijd, complementair, immuuntherapie, virus Ankara–5T4, TroVax, cyclophopsphamide