Kanker in onze hersenen: hoe kan het immuunsysteem helpen?
Hoe komt het dat de huidige behandelingsstrategie voor glioblastoma, de meest agressieve hersentumor, niet in staat is patiënten te genezen en wat is de belangrijke rol van het immuunsysteem in dit verhaal?
Wat is glioblastoma?
Glioblastoma is de meest voorkomende en meest agressieve vorm van kanker in onze hersenen. Het is gelukkig zeldzaam, slechts 500 patiënten in België per jaar, maar de ziekte treft ook jonge kinderen. De standaardbehandeling bestaat uit een operatie waarbij de kanker zo goed mogelijk wordt weggesneden, gevolgd door een combinatie van bestralingen (radiotherapie) en chemotherapie (in de vorm van Temozolomide). Ondanks het intensieve karakter van deze behandeling, is ze tot op heden niet in staat om patiënten te genezen. Glioblastoma patiënten hebben daarom een zeer slechte overleving van gemiddeld 14 maanden. Verschillende onderzoekers zijn om deze reden al een lange tijd op zoek naar een nieuwe en betere behandeling die de vooruitzichten voor deze patiënten in sterke mate zou kunnen verbeteren.
Wat is de rol van het immuunsysteem in dit verhaal?
Het immuunsysteem in ons lichaam zorgt ervoor dat we ons kunnen verdedigen tegen een waaier aan ziektes veroorzaakt door virussen (bijvoorbeeld griep) of bacteriën (bijvoorbeeld een longontsteking), maar eigenlijk kan het immuunsysteem ook beschermen tegen kanker. Het bestaat uit een reeks verschillende cellen die elk een andere belangrijke functie uitoefenen. Al die verschillende cellen werken gecoördineerd samen om kankercellen te herkennen en uit de weg te ruimen.
Hoe komt het dan dat er toch een tumor kan uitgroeien? Tumorcellen zijn slim en kunnen zich zeer goed aanpassen aan hun omgeving. Ze kunnen hun uiterlijke kenmerken veranderen zodat ze bijna onherkenbaar worden voor ons immuunsysteem, een fenomeen dat we immuun onderdrukking noemen. Eén van de manieren waarop kankercellen ons immuunsysteem kunnen ontwijken, is bijvoorbeeld door het aanmaken van een molecule genaamd PD-L1. Dit molecule blokkeert de werking van immuuncellen, die normaal in staat zouden zijn een kankercel uit de weg te ruimen. Dit is ook wat zich voordoet bij glioblastoma. Deze agressieve kankercellen zijn specialisten in het zich verstoppen voor ons immuunsysteem, wat het natuurlijk moeilijk maakt voor ons lichaam om hier op te reageren. Deze complexe wisselwerking tussen het immuunsysteem en kankercellen maakt het voor onderzoekers een serieuze uitdaging om een nieuwe behandeling te vinden.
Welke nieuwe therapieën zouden ons kunnen helpen?
De laatste jaren zijn verschillende onderzoeksgroepen druk bezig geweest om nieuwe therapieën te ontwikkelen die het immuunsysteem opnieuw kunnen activeren tegen die kankercellen. Eén zo een strategie is de ontwikkeling geweest van immuun checkpoint remmers (anti-PD(L)1). Ze heffen de blokkering op tussen kankercellen en immuuncellen die op basis van PD-L1 tot stand is gekomen. Daardoor zouden de immuuncellen theoretisch terug aan het werk moeten kunnen gaan (omdat ze terug ‘vrij’ zijn) en dus kankercellen moeten kunnen doden. Deze specifieke therapie is zeer succesvol bij huidkanker en longkanker bijvoorbeeld. Het is reeds getest bij glioblastoma patiënten in combinatie met de huidige behandeling (een operatie, bestraling en chemotherapie), maar jammer genoeg kan het succesverhaal van huidkanker en longkanker niet worden doorgetrokken. Mensen met hersenkanker gaan even snel dood, met of zonder deze speciale remmers.
Waarom falen deze therapieën?
Om te weten te komen waarom deze nieuwe combinatie van anti-PD-1 en de standaardbehandeling niet werkt, moeten we nagaan wat er precies gebeurt in patiënten met een hersentumor. Om deze informatie te verkrijgen, hebben wij muizen met hersentumoren bestudeerd en gekeken hoe zij reageren op al deze therapieën. Dit is een cruciale stap om aan het licht te brengen wat er zich bij de mens afspeelt. In dit onderzoek zijn wij te weten gekomen dat alle behandelingen (zowel de bestraling, de chemotherapie en de anti-PD-1) afzonderlijk een zeer uitgesproken effect hebben.
Zo hebben we kunnen vaststellen dat bestraling het grootste immuun stimulerende effect heeft. Dit betekent dat het immuunsysteem een enorme boost krijgt en dus beter kan gaan werken. Dit positieve effect op het immuunsysteem vertaalt zich ook in het feit dat muizen die bestraald worden, langer leven. Chemotherapie daarentegen veroorzaakt echter het tegengestelde effect. Het vermindert de werking van het immuunsysteem en legt het voor een deel lam. Dit gaat zelfs zo ver dat de combinatie van bestraling met chemotherapie (hetgeen elke patiënt momenteel krijgt als standaard behandeling) de positieve effecten van de bestraling volledig teniet doet. Meer nog, dit immuun onderdrukkend effect is zo uitgesproken, dat de immuuntherapie met anti-PD-1 niet in staat is om het immuunsysteem opnieuw te activeren wanneer het in combinatie wordt gegeven met de bestraling en de chemotherapie.
Uit deze resultaten blijkt dat het immuun onderdrukkende effect van de chemotherapie die gebruikt wordt in patiënten met hersentumoren, wel eens de reden zou kunnen zijn waarom anti-PD-1 in de kliniek geen bijkomend voordeel biedt aan deze patiënten. Het toont aan dat het immuunsysteem belangrijker is dan ooit tevoren in het bestrijden van glioblastoma, en bij uitbreiding kanker in het algemeen. De grootste uitdaging in de toekomst voor ons, onderzoekers, zal zijn om de immuun onderdrukkende effecten van de kankercellen om te keren en te zorgen voor een meer immuun stimulerende omgeving in het voordeel van de patiënt.
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