2_arnCancer
π Health and biotech
Beyond Covid: the promise of mRNA vaccines

An mRNA vaccine against cancer?

Agnès Vernet, Science journalist
On December 8th, 2021 |
3 mins reading time
2
An mRNA vaccine against cancer?
Suzy Scholl
Suzy Scholl
Director of the international RAIDS network at Institut Curie
Key takeaways
  • Malignant tumours stimulate the production of a “shield” around it made from blood vessels, called “neovascularisation”. This weakens the immune response to the tumour, making the body more tolerant to it.
  • The immunostimulatory properties of mRNA allows the immune system to be re-trained so that it can recognise one or more markers of cancer cells. Therefore, we talk about an “anti-cancer” vaccine.
  • From a medical point of view, these tailor-made therapies are interesting, but the prototypes are likely to be very expensive and will be reserved for patients treated in centres with expertise in immunotherapy.
  • Advanced tumours can metastasise despite one or more treatments. If mRNA molecules continue to be successfully developed, they will complement the current therapeutic arsenal, combined with other targeted therapies, and thus, hopefully, further reduce the mortality of these diseases.

More than 300,000 new can­cers are diag­nosed in France each year, with over 150,000 deaths attrib­ut­able to them. Although clin­i­cal research has made sig­nif­i­cant progress over the last few decades, enabling more accu­rate diag­no­sis, bet­ter treat­ment and even a cure for cer­tain types of tumours, the need for new ther­a­pies remains immense. Mol­e­c­u­lar biol­o­gy has shown that can­cers are caused by an accu­mu­la­tion of alter­ations in the genome of cells through­out life, which in the long term can lead to uncon­trolled cell pro­lif­er­a­tion. But malig­nant tumours use oth­er strate­gies to spread. For exam­ple, they mod­i­fy their ‘microen­vi­ron­ment’ in order to build a new net­work of small blood ves­sels around them, pro­vid­ing them with the nutri­ents they need. This ‘neo­vas­cu­lar­i­sa­tion’ has anoth­er effect: it pro­tects the tumours from the immune sys­tem by cre­at­ing a kind of shield. The effec­tive immune response is thus weak­ened, and the body begins to tol­er­ate the tumour.

The immunos­tim­u­la­to­ry prop­er­ties of syn­thet­ic mes­sen­ger RNA (mRNA) can help to cor­rect this phe­nom­e­non. This strat­e­gy con­sists of pro­duc­ing mRNAs cod­ing for pro­teins con­sid­ered for­eign to the nor­mal patient, known as “tumour epi­topes”. These mol­e­cules can be con­sid­ered as immune bio­mark­ers of tumours. When the immune sys­tem recog­nis­es these pro­teins, it reacts almost as it would to pathogens (virus­es or microbes), keep­ing these mark­ers in mem­o­ry. This is why these mRNAs are described as can­cer vac­cines. By inject­ing patients with these vac­cines, the aim is not to vac­ci­nate against a pathogen, but to retrain the immune sys­tem to recog­nise one or more mark­ers of can­cer cells. The spe­cif­ic mark­er, or mark­ers, still need to be identified.

A complex task, but not an impossible one

Can­cers use mul­ti­ple path­ways to devel­op and have great plas­tic­i­ty. It is there­fore cru­cial to study the genome of each patient’s tumour to iden­ti­fy rel­e­vant tumour epi­topes. From a med­ical point of view, these tai­lor-made ther­a­pies are inter­est­ing, but the pro­to­types are like­ly to be very expen­sive and will be reserved for patients treat­ed in cen­tres with exper­tise in immunother­a­py, since their imple­men­ta­tion is so technical.

To sim­pli­fy the field of inves­ti­ga­tion, bio­med­ical com­pa­nies are con­sid­er­ing the pro­duc­tion of mRNAs tar­get­ing com­mon and well-known tumour anti­gens. The Ger­man com­pa­ny BioN­Tech, which became known for hav­ing devel­oped the anti-Covid vac­cine with Pfiz­er, is lead­ing the way in these pro­grammes. It already has sev­er­al mRNA can­di­dates that have been stud­ied in haema­to­log­i­cal tumours as well as in numer­ous sol­id tumours.

Among the tumour anti­gen epi­topes, some are com­mon to can­cers occur­ring in dif­fer­ent organs. This is the case, for exam­ple, of cer­tain mem­brane recep­tors such as EGFR (HER1) or HER (2, 3 or 4), which are present and often acti­vat­ed (by dif­fer­ent mol­e­c­u­lar mech­a­nisms) in many ade­no­car­ci­no­mas, i.e. in sub­groups of breast, prostate, thy­roid, pan­cre­at­ic, ovar­i­an, kid­ney, liv­er and col­orec­tal can­cers. How­ev­er, in advanced tumours, oth­er onco­genes are activated.

A market launch in the near future?

Most of these vac­cine can­di­dates are cur­rent­ly in Phase 1 or 2 clin­i­cal tri­als, test­ing their safe­ty and effi­ca­cy against metasta­t­ic melanoma, head and neck can­cer, ovar­i­an tumours, and col­orec­tal can­cers. While it is usu­al to do a phase‑3 study com­par­ing the vac­cine to pre­vi­ous “stan­dard” treat­ments before apply­ing for mar­ket­ing autho­ri­sa­tion, in the case of these vac­cines this may not be pos­si­ble. It is indeed eth­i­cal­ly ques­tion­able to con­struct a clin­i­cal tri­al where some patients are treat­ed with a con­ven­tion­al chemother­a­py empir­i­cal­ly devel­oped in the clin­ic on the basis of a response rate and dura­tion of response. Fre­quent­ly used con­ven­tion­al chemother­a­pies act by impair­ing cel­lu­lar func­tions, for exam­ple by pre­vent­ing DNA repair, or by block­ing the mitot­ic spin­dle, but resis­tance to these mech­a­nisms is only begin­ning to be elucidated.

In the con­text of advanced tumours with mul­ti­ple alter­ations, it may also be very com­plex to con­struct groups for com­par­i­son, i.e. with patients shar­ing exact­ly the same mol­e­c­u­lar abnor­mal­i­ties in the active and con­trol arms. These inno­va­tions could there­fore poten­tial­ly reach the mar­ket on the basis of strong phase‑2 data.

Ulti­mate­ly, advanced tumours are high­ly het­ero­ge­neous and at the same time high­ly plas­tic. When they spread through­out the body, form­ing metas­tases, despite the admin­is­tra­tion of one or more treat­ments, the ‘per­sis­tent’ tumour cells are remark­able for their adapt­abil­i­ty and for the pres­ence of many defects that pre­vent them from dying. In this sit­u­a­tion, it is com­mon­ly accept­ed that the can­cer will need to be tar­get­ed by mul­ti­ple approach­es in com­bi­na­tion. A very large num­ber of lab­o­ra­to­ries are inter­est­ed in RNAs for future can­cer treat­ments. If suc­cess­ful­ly devel­oped, they will com­ple­ment the cur­rent ther­a­peu­tic arse­nal, com­bin­ing with oth­er tar­get­ed ther­a­pies to fur­ther reduce mor­tal­i­ty rates for these diseases.