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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)
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:
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:
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 identifier | Setting | Phase | Study interventions | Number of patients | Primary 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:
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 safetyLees ook dit artikel:
The emerging role of immunotherapy in colorectal cancerFrom 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 Tables111–3. 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
This article has been cited by other articles in PMC.
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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Articles from Journal of Cancer are provided here courtesy of Ivyspring International Publisher
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