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28 september 2017: Bron: J Cancer. 2016; 7(12): 1599–1604 en Biomed Res Int. 2017; 2017: 4346576.

Al eind jaren negentig en begin jaren 2000 werden ook in Nederland en België studies uitgevoerd met immuuntherapie bij darmkanker en andere vormen van spijsverteringskanker als alvleesklierkanker, en maagkanker en slokdarmkanker. Sommige met succes andere zonder succes. (Tekst gaat verder onder foto)

immuuntherapie
De belangrijkste studie naar de effecten van immuuntherpie was in 1999 in The Lancet gepubliceerde fase III studie van Vermorken J. B., Claessen A. M. E., Van Tinteren H., et al. Active specific immunotherapy for stage II and stage III human colon cancer: A randomised trial. Lancet. 1999;353(9150):345–350. doi: 10.1016/S0140-6736(98)07186-4 die ook jarenlang werd vermeld in oncoline maar daaruit inmiddels is verwijderd.

Maar in deze studie werd een 44% vermindering van het risico op een recidief gezien wanneer patiënten met darmkanker  werden behandeld met Oncovax (p = 0.023). In een subgroep van patienten met een stadium II van darmkanker was dat risico zelfs met 61% verminderd. Maar om welke reden dan ook is die aanpak vanuit die studie nooit echt doorgezet, zie onder autovaccinatie op onze site. Onterecht m.i.

Uit het studieverslag over Oncovax:

De werkzaamheid van OncoVAX werd vervolgens geëvalueerd in de adjuvante setting in drie fase III klinische studies waarbij patiënten gerandomiseerd werden ingedeeld om alleen een operatie te ondergaan  of een operatie gevolgd door een autovaccinatie met Oncovax.
De eerste studie (8102) werd in 1981 gestart en 98 patiënten met darmkanker in stadium II en III namen deel. De primaire einddoelen, overall overleving (OS) en ziektevrije overleving (DFS) werden niet bereikt (HR voor OS = 1,75, p = 0,68; HR voor DFS = 1,58, p = 0,147).
In de subgroepanalyses werd echter een statistisch significant voordeel van OncoVAX gezien bij patiënten met dikke darmkanker (HR voor OS = 2,83, p = 0,02; HR voor DFS = 2,67, p = 0,039) maar niet bij patiënten met rectale kanker (HR voor OS = 1,13, p = 0,772; HR voor DFS = 1,05, p = 0,905).

In de fase III 5283 studie met totaal 412 darmkankerpatiënten met stadium II en III werden er statistisch geen verschillen in overall overleving (OS) en ziektevrije tijd (DFS) waargenomen.

Tenslotte werden in de fase 8701 III studie 254 patiënten met darmkanker stadium II en III gerandomiseerd ingedeeld en onderzocht wat de resultaten op overall overleving (OS) en ziektevrije tijd (DFS) zouden zijn als het vaccin 4 keer werd toegediend in plaats van 3 keer. In die studie werd een 44% verminderd risico gezien op een recidief bij patiënten die werden behandeld met OncoVAX (p = 0,023). In de subgroepanalyses werd een nog betere werkzaamheid waargenomen bij patiënten met stadium II (61% risicoreductie op een recidief).

Een meta-analyse, inclusief de 3 hierboven vermelde onderzoeken, vertoonde een verbetering van het risico op een recidief door OncoVAX met een jaarlijkse kansverlaging van 25 ± 13% (p = 0,05). De subgroepanalyse per stadium vertoonde een statistisch significante verbetering bij stadium II patiënten (p = 0,05).

Een andere studie liet zien dat dendritische celtherapie met het Newcastle Disease Virus ook goede resultaten liet zien. Niet bij rectale vormen van kanker maar wel bij dikke darmkanker:

De resultaten van een gerandomiseerde fase III trial met een NDV autoloog gemodificeerd vaccin bij patiënten die een radicale resectie van levermetastasen vanuit darmkanker hadden ondergaan, werden eind 2000 gepubliceerd. Aan deze studie namen 51 patiënten deel. Er werden statistisch geen significante verschillen in overall overleving (OS) en in ziektevrije tijd (DFS) geconstateerd. Maar in de subgroepanalyses werd wel een statistisch significant voordeel waargenomen bij patiënten met dikke darmkanker met betrekking tot overall overleving (OS) (HR 3.3, p = 0.042) en ziektevrije tijd (DFS) (HR 2.7, p = 0.047), Maar ook hier niet bij patiënten met rectale kanker. Waarom niet wordt niet beschreven. Zie deze studie: 

Schulze T., Kemmner W., Weitz J., Wernecke K.-D., Schirrmacher V., Schlag P. M. Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: Results of a prospective randomized trial. Cancer Immunology, Immunotherapy. 2009;58(1):61–69

Inmiddels zijn naast de immuuntherapeutische studies met autovaccinatie en dendritische celtherapie en andere vaccins er ook andere aanpak met immuuntherapie met anti-PD medicijnen bijgekomen.

En met succes.

Zo blijkt uit de Checkmate 142 studie waarin o.a. nivolumab wel en niet wordt gecombineerd met ipilimumab:

72 patiënten behandeld met nivolumab gaven hoopgevende resultaten op 12 maanden meting met een ziektevrije overleving van 48,4% en overall overleving 73.8%. Zelfs 2 patienten bereikten binnen een jaar een complete remissie. 

Results: 70 (N3) and 30 (N3 + I1) MSI-H pts and 3 (N1 + I1), 10 (N1 + I3), and 10 (N3 + I1) non-MSI-H pts were enrolled. All non-MSI-H pts and 87% (N3) and 93% (N3 + I1) of MSI-H pts had ≥2 prior regimens. 47 (67%; N3) and 18 (60%; N3 + I1) MSI-H pts remain on tx. Efficacy data for MSI-H pts are shown in the Table. Responses were also seen in non-MSI-H pts. Median (95% CI) PFS across all non-MSI-H pts was 1.4 mo (1.2, 1.9). Responses were observed regardless of tumor PD-L1 expression. Treatment-related adverse events (TRAEs) occurred in 41 (59%; N3) and 25 (83%; N3 + I1) MSI-H pts; 10 (14%; N3) and 8 (27%; N3 + I1) pts had Grade 3–4 TRAEs. One pt on N3 had a Grade 5 TRAE (sudden death). Additional biomarker data including MSI assessment and influence of BRAF/KRAS mutations will be presented.

En immuuntherapie met een gemoduleerd virus liet op ESMO 2017 ook uitstekende resultaten zien, zoals we al eerder hebben gepubliceerd op kanker-actueel: 

https://kanker-actueel.nl/NL/immuuntherapie-met-het-gemoduleerde-virus-ankara5t4-trovax-plus-lage-dosis-cyclophosphamide-zorgt-voor-verdubbeling-van-mediane-overall-overleving-112-vs-20-maanden-bij-vergevorderde-darmkanker.html

Saemnvattend zien we dat immuuntherapie bij vormen van spijsverteringskanker op de goede weg is. Ook in Nederland en België.

Hier een aantal studies met immuuntherapeutische aanpak die al klaar zijn of die nog lopen. Klik op de NCT nummers voor studieprotocollen:

Table 1

Ongoing studies on gastric, gastroesophageal junction, and esophageal cancers.

NCT identifierSettingPhaseStudy interventionsNumber of patientsPrimary endpoint
Checkpoint inhibitors
NCT02689284 Metastatic HER2+ GC/GEJC Ib/II Margetuximab+ pembrolizumab 52 MTD and MAD for margetuximab; duration of response; 12-month ORR
NCT02563548 Metastatic GC after 1st line Ib PEGPH20 +pembrolizumab 81 DLT; 18-month ORR
NCT02443324 Metastatic GC/GEJC and other tumours I Ramucirumab + pembrolizumab 155 DLT
NCT02589496 Metastatic GC/GEJC after first line II Pembrolizumab 40 2-year RR
NCT02901301 First-line HER2 + GC Ib/II Pembrolizumab + trastuzumab + capecitabine + cisplatin 49 RP2D; 6-week ORR
NCT02954536 First-line HER2+ GC/GEJC/EC II Pembrolizumab + trastuzumab + capecitabine + cisplatin 37 6-month PFS
NCT02318901 Unresectable HER2 + GC/GEJC II Pembrolizumab + ado-trastuzumab emtansine 90 RP2D
NCT02559687 EC (adenocarcinoma or squamous cell)/GEJC after 2nd line II Pembrolizumab 100 2-year ORR
NCT02494583 First-line GC/GEJC III (random) Pembrolizumab versus pembrolizumab + cisplatin + 5-fluorouracil or capecitabine versus placebo + cisplatin + 5-FU or capecitabine 750 44-month PFS and OS
NCT02370498 Second-line GC/GEJC III (random) Pembrolizumab versus paclitaxel 720 PFS, OS
NCT02564263 EC (adenocarcinoma or squamous cell) /GEJC after 1st line III (random) Pembrolizumab versus investigator's choice of standard therapy (paclitaxel, docetaxel, or irinotecan) 600 3-year PFS and OS
NCT02872116 Unresectable GC/GEJC III (random) Nivolumab + ipilimumab versus nivolumab + oxaliplatin + fluoropyrimidine versus oxaliplatin + fluoropyrimidine 1266 40-month OS in patients PD-L1 +
NCT02864381 Metastatic GC/GEJC II (random) GS-5745 + nivolumab versus nivolumab alone 120 2-year ORR
NCT02340975 Pretreated metastatic/GC/GEJC Ib/II (random) MEDI4736 + tremelimumab versus MEDI4736 versus tremelimumab 135 Phase Ib: DTL,
Phase II: ORR and 6-month PFS
NCT02625623 3rd-line GC/GEJC III (random) Avelumab+ BSC versus chemotherapy (paclitaxel or irinotecan)+BSC or BSC alone 330 2-year OS
NCT02625610 1st-line GC/GEJC III (random) Maintenance with avelumab versus continuation of 1st-line chemotherapy 666 3-year OS and PFS

Immunotherapy + radiotherapy
NCT02642809 1st-line EC I Pembrolizumab + brachytherapy 15 Tolerability and toxicity
NCT02830594 Pretreated EC/GC(GEJC II Pembrolizumab + external beam palliative radiation therapy 14 Biomarkers
NCT02735239 Metastatic EC I/II Durvalumab + oxaliplatin/capecitabine 75 AE, DLT, laboratory evaluations
Vaccines
NCT02276300 Metastatic HER 2 + GC I HER2-derived peptide vaccination 12 Safety and tolerability
NCT02317471 Stage III gastric cancer I/II Vaccination with autologous tumour derived heat shock protein gp96 45 DFS
NCT02795988 Metastatic HER 2 + GC/GEJC Ib/II IMU-131 HER2/Neu peptide vaccine+ cisplatin and either 5-FU or capecitabine chemotherapy 18 RP2D, AE
Cytokines
NCT01691664 Locally advanced EC NS (random) Radiation therapy alone or with DC-CIK cellular therapy 40 DFS
NCT01691625 Locally advanced EC NS (random) Concurrent chemoradiation with or without DC-CIK 50 Quality of life
NCT02504229 Metastatic refractory GC II
(random)
Chemotherapy with or without DC-CIK 80 PFS
NCT01783951 Metastatic refractory GC I/II S-1 with or without DC-CIK 30 PFS

CAR-T cells
NCT02713984 Metastatic refractory HER 2 + GC I/II Anti-HER2 CAR-T cells 60 Toxicity
NCT02725125 Metastatic refractory GC I/II EPCAM-targeted CAR-T cells 19 DCR
NCT02617134 Metastatic refractory MUC1+ GC I/II Anti-MUC1 CAR-T cells 20 Toxicity
NCT02349724 Metastatic refractory CEA+ GC I Anti-CEACAR-T cells 75 Toxicity
NCT02862028 Metastatic refractory EGFR+ GC I/II Anti-PD-1CAR-T cells 20 ORR, DCR, OS, PFS
NCT03013712 Metastatic refractory EpCAM+ GC/EC I/II Anti-EpCAMCAR-T cells 60 Toxicity

GC, gastric cancer; GEJC, gastroesophageal junction cancer; EC: esophageal cancer; NA, not assessed; MTD, maximum tolerated dose; MAD, maximum administered dose; DTL, dose limiting toxicity; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; DFS, disease-free survival; NS, not specified; RP2D, recommended dose of phase II; AE, adverse events; DCR, disease control rate; BSC, best supportive care; DCR disease control rate.

Het volledige studierapport: Current Status and Perspective of Immunotherapy in Gastrointestinal Cancers is gratis in te zien. Evenals het studierapport: Immunotherapy in Gastrointestinal Cancers

Abstracten van beide studies plus referentielijsten volgen onderaan dit artikel.

Lees ook dit artikel: 

https://kanker-actueel.nl/NL/pole-mutatie-veel-kankerpatienten-met-erfelijke-vormen-van-kanker-hebben-naast-een-p1-ligand-een-pole-mutatie-en-reageren-goed-op-immuuntherapie-met-anti-pd-medicijnen-checkpointremmers-als-pembrolizumab-en-nivolumab.html

En lees ook de richtlijnen voor het behandelen van uitgezaaide darmkanker  zoals gepubliceerd door de ESMO: 

Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Interessant is ook deze review over zogeheten oncolytische virussen: 

Oncolytic viruses: From bench to bedside with a focus on safety

Lees ook dit artikel: 

The emerging role of immunotherapy in colorectal cancer

From a clinician perspective, the use of immunotherapies in recent clinical trials gave us the opportunity to contribute to a paradigmatic shift in the treatment of GI cancers. We are glad to observe highly pretreated patients experiencing a dramatic clinical benefit after treatment start, with symptoms relief, long lasting disease stabilization, and an overall manageable safety profile.

Biomed Res Int. 2017; 2017: 4346576.
Published online 2017 Jul 3. doi:  10.1155/2017/4346576
PMCID: PMC5512095

Immunotherapy in Gastrointestinal Cancers

Abstract

Gastrointestinal cancers represent a major public health problem worldwide. Immunotherapeutic strategies are currently under investigation in this setting and preliminary results of ongoing trials adopting checkpoint inhibitors are striking. Indeed, although a poor immunogenicity for GI has been reported, a strong biological rationale supports the development of immunotherapy in this field. The clinical and translational research on immunotherapy for the treatment of GI cancers started firstly with the identification of immune-related mechanisms possibly relevant to GI tumours and secondly with the development of immunotherapy-based agents in clinical trials. In the present review a general overview is firstly provided followed by a focus on major findings on gastric, colorectal, and hepatocellular carcinomas. Finally, pathological and molecular perspectives are provided since many efforts are ongoing in order to identify possible predictive biomarkers and to improve patients' selection. Many issues are still unsolved in this field; however, we strongly believe that immunotherapy might positively affect the natural history of a subgroup of GI cancer patients improving outcome and the overall quality of life.

Finally the most efforts are focusing on the development of novel approaches to enhance this innovative strategy. All ongoing trials are shown in Tables Tables1113. Promising trials have been evaluating innovative combination treatments (so-called “combo-immunotherapy”), that is, PD-1 or PD-L1 blockade in combination with (1) anti-CTLA4, (2) adaptive immunotherapy such as anti-LAG3, (3) innate immunotherapy such as TLRs agonists, (4) chemo- or radiotherapy, (5) drugs able to increase antigen presentation such as the COX-2, JAK1/2 inhibitor or the MEK inhibitor cobimetinib, and (6) targeted therapy (anti-HER2, anti-VEGFR2) [69, 114, 115].

From a clinician perspective, the use of immunotherapies in recent clinical trials gave us the opportunity to contribute to a paradigmatic shift in the treatment of GI cancers. We are glad to observe highly pretreated patients experiencing a dramatic clinical benefit after treatment start, with symptoms relief, long lasting disease stabilization, and an overall manageable safety profile. We are really feeling a revolution in the daily life of our patients. Every day we ask questions about future availability of clinical trials involving immunotherapeutic agents for GI cancers from our new and historical patients. We strongly believe that further steps of drugs development such as larger phases II and III clinical trials are warranted in order to answer unsolved question and to establish the efficacy of immunotherapeutic agents. A wide international involvement of experienced centers in the next clinical trials will break a potential unequal distribution of immunotherapeutic resources.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors' Contributions

Letizia Procaccio and Marta Schirripa equally contributed as first authors. Vittorina Zagonel and Sara Lonardi equally contributed as senior authors.

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Articles from BioMed Research International are provided here courtesy of Hindawi

Current Status and Perspective of Immunotherapy in Gastrointestinal Cancers

J Cancer. 2016; 7(12): 1599–1604.
Published online 2016 Jul 18. doi:  10.7150/jca.16208
PMCID: PMC5039380

Current Status and Perspective of Immunotherapy in Gastrointestinal Cancers

Abstract

Cancer immunotherapy is at dawn of the Renaissance after the Medieval Dark Ages. Recent advances of understanding tumor immunology and molecular drug development are leading us to the epoch of cancer immunotherapy. Some types of immunotherapy have shown to provide survival benefit for patients with solid tumors such as malignant melanoma, renal cell carcinoma, or non-small cell lung cancer. Several studies have suggested that immune checkpoint inhibition might be effective in some patients with gastrointestinal cancers. However, the era of cancer immunotherapy in gastrointestinal cancers is still in an inchoate stage. Here we briefly review the current status and perspective of immunotherapeutic approaches in patients with gastrointestinal cancers.

Conclusion

Cancer immunotherapy has shown promising results in various types of cancers. Especially immune checkpoint inhibitors are leading a recent renaissance of immune-mediated anticancer treatments. Early studies have suggested that immune checkpoint inhibition might also be effective in some patients with gastrointestinal cancers. However, the era of cancer immunotherapy in gastrointestinal cancers is in an inchoate stage. The immune system and immunosuppressive mechanisms surrounding GC or CRC are still obscure compared to malignant melanoma, renal cell carcinoma, or NSCLC. To increase efficacy of cancer immunotherapy in gastrointestinal cancers, we need to build more profound understanding of tumor immune system. Knowledge of potential relationships between tumor cells and their microenvironment is also essential in gastrointestinal malignancies.

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