Bodmer Walter, Golubovskaya Vita
Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, UK.
Promab Biotechnologies, Richmond, CA 94806, USA.
Cancers (Basel). 2023 Apr 18;15(8):2358. doi: 10.3390/cancers15082358.
The fundamental problem of dealing with cancer is that cancer cells are so like normal cells that it is very hard to find differences that can be a basis for treatment without severe side effects. The key to successful cancer immunotherapy will be based on a very careful choice of cancer targets that are sufficiently cancer specific not to cause serious side effects. There are two fundamentally different ways to deploy the immune system for such cancer treatments. One is to increase the efficacy of the cancer patient's own immune system so that it attacks these differences. This has been achieved by "checkpoint blocking" which is very successful but only with a relatively small proportion of cancers. Secondly, one can produce antibodies, or T cells, whose specificity is directed against proteins expressed differentially in cancers. CART cell treatments have proved very effective for some blood cancers but not so far for common solid tumours. Humanised, unmodified monoclonal antibodies have been used extensively for the treatment of certain adenocarcinomas with modest success. However, using antibodies together with the body's own immune system to treat cancers by engineering monoclonal antibodies that are directed at both a target antigen on the cancer cell surface and also against T cells shows promise for the development of novel immunotherapies. Genes can be found which are expressed highly in some cancers but with a low or absent expression on normal tissues and so are good novel targets. It is so far, only immune-based killing that can kill bystander target negative cells, which is essential for successful treatment since hardly ever will all the cells in a cancer express any desired target. We conclude that, while there still may be many hurdles in the way, engineered bispecific T cell attracting monoclonal antibody-mediated killing of cancer cells may be the most promising approach for achieving novel effective cancer immunotherapies.
治疗癌症的根本问题在于癌细胞与正常细胞极为相似，以至于很难找到能够作为治疗基础且无严重副作用的差异。成功的癌症免疫疗法的关键将基于对癌症靶点的非常谨慎的选择，这些靶点要具有足够的癌症特异性以避免引起严重的副作用。有两种根本不同的方式来为这种癌症治疗调动免疫系统。一种是提高癌症患者自身免疫系统的功效，使其攻击这些差异。这已通过“检查点阻断”得以实现，该方法非常成功，但仅适用于相对较小比例的癌症。其次，可以产生特异性针对癌症中差异表达蛋白质的抗体或T细胞。嵌合抗原受体（CART）细胞疗法已被证明对某些血液癌症非常有效，但迄今为止对常见实体瘤效果不佳。人源化、未修饰的单克隆抗体已被广泛用于治疗某些腺癌，取得了一定的成功。然而，通过设计既针对癌细胞表面的靶抗原又针对T细胞的单克隆抗体，将抗体与人体自身免疫系统结合起来治疗癌症，显示出开发新型免疫疗法的前景。可以找到在某些癌症中高表达但在正常组织中低表达或不表达的基因，因此这些基因是很好的新型靶点。到目前为止，只有基于免疫的杀伤能够杀死旁观者靶阴性细胞，这对于成功治疗至关重要，因为癌症中的所有细胞几乎不可能都表达任何所需的靶点。我们得出结论，虽然道路上可能仍然存在许多障碍，但工程化双特异性T细胞吸引单克隆抗体介导的癌细胞杀伤可能是实现新型有效癌症免疫疗法最有前景的方法。
