A study published in Nature looks at non-viral precision T cell receptor replacement using CRISPR technology for personalized cell therapy.
Prof Waseem Qasim, NIHR Professor in Cell & Gene Therapy and Consultant in Paediatric Immunology, UCL Institute of Child Health & Great Ormond Street Hospital, said:
“This is of interest because it brings together various bits of cutting edge technology to create a new therapeutic approach where a patient’s own immune cells (T cells) are reprogrammed against proteins from their own cancers. That’s an approach being investigated in various guises, but the application of CRISPR gene editing allowed the scientists to slip new T cell receptors exactly into the place of existing ones. While the clinical responses were limited, the paper is a powerful early demonstration of what might be possible with newer techniques.”
Dr Astero Klampatsa, Team Leader of the Thoracic Oncology Immunotherapy Group at The Institute of Cancer Research, London, said:
“T-cell therapy involves taking a patient’s T-cells, genetically modifying them in a lab to make them better at finding and killing cancer cells, and then re-infusing them to the patient through the bloodstream with a drip. This strategy has shown remarkable success in blood cancers. But current findings suggest the successes of T-cell therapy in blood cancers cannot be replicated in solid tumours. Due to the limitations that the complex nature of solid cancers pose to these therapies, more sophisticated approaches in the development of T-cell therapies are needed.
“This study published today is important, as the first human trial in solid cancers showcasing the use of patient-specific, CRISPR-engineered T cells that are able to identify specific antigens, or ‘flags’ on the patient’s tumour cells, prompting them to kill them.
“The study suggests there is future potential for T-cell therapy in solid cancers, and its safety profile is certainly encouraging; however there are also limitations that even the authors note: the time, labour and expense involved in the processes required to develop this therapy are huge and risky. It would be interesting to see whether this therapy will be applied in a bigger trial, where efficacy, but also the experimental protocols, can be further tested.”
Comments from our friends at the Spanish SMC:
Manel Juan, Head of the Immunology Service of Clínic Hospital, said:
“It is an extraordinary work, undoubtedly one of the most advanced in the field of adoptive cellular immunotherapy (ACTI) both technically and conceptually, and opens the door to the most personalized approach possible for the treatment of tumors. This is not the first study to test the CRISPR tool for the first time to modify T lymphocytes (as the authors themselves mention, this has already been done with CART), but it is the first to do so with the patient’s own T lymphocyte receptors (TCRs), thus managing to direct them against specific antigens of each tumor in each patient.
The work defines how we can genetically modify other lymphocytes from the patient’s own blood with various receptors of antitumor T lymphocytes, so that they can be directed against the tumor. The work manages to merge in one proposal the best of the three already successful ITCA approaches, the infusion of tumor infiltrating lymphocytes (TIL therapy), the use of transgenic TCRs and the genetic modification of T lymphocytes with gene editing. Although the focus on TCRs of cytotoxic CD8+ T lymphocytes is obviously a first step and leaves in second place the need to obtain TCRs for CD4+ T cells, which we know are relevant especially in long-term treatments, the proposal allows to raise a personalized treatment scenario for many tumors.
It opens the door to using this personalized ITCA in many types of cancer and potentially in many other diseases defined by the function of the immune system. The good development of ITCA in our country (especially in CART therapy) may make it possible to provide this option to our patients in such a personalized way that it can be considered as an academic treatment”.
Josep Tabernero, Head of the Oncology Department of the Vall d’Hebron University Hospital of Barcelona and Director of the Vall d’Hebron Institute of Oncology, said:
“This is a great study, seminal and of excellent quality. It is a pioneering work because of the technology applied to modify these lymphocytes and make these TCRs [T lymphocyte receptors] using CRISPR/Cas9 gene editing technology instead of viral vectors, which are always more complex, and because of the biological proof of concept demonstrated in tumor biopsies, with the presence of these modified lymphocytes with NeoTCRs in the tumor. In addition, the authors silenced (knock-out) their own TCRs (alpha and beta) and constructed the new specific one (neoTCR) to give it greater selectivity and specificity. The study opens the door to a new way to modify lymphocyte TCRs and to select the neoantigens [targets present only in tumor cells] toward which these TCRs are directed by means of a bioinformatics algorithm, in a more efficient way.
This is a very important step in the field of adoptive cell therapy with modified lymphocytes (NeoTCRs) to help more and more patients with solid tumors to benefit from these treatments. Until now, the different cellular immunotherapy technologies have mainly focused on patients with hematological tumors. For the time being, antitumor activity is modest, but it is a clear proof of concept to be improved in the future.
As for the limitations, the authors are very elegant in clearly showing the complexity of the process and the limitations of the technology. Of 187 initial patients who sign the consent form, only 16 patients are ultimately able to be treated. Many of these complexities and limitations are very amenable to future improvements in patient enrichment and selection (less advanced disease and access to tumor samples with better tumor content) and improved technology”.
‘Non-viral precision T cell receptor replacement for personalized cell therapy’ by Susan P. Foy et al. was published in Nature at 16:00 UK time on Thursday 10 November 2022.
Prof Waseem Qasim: “Not involved in the research or connected to the group/company. Do hold patents around T cell engineering and have advised other companies developing cancer cell therapies.”
Dr Astero Klampatsa: “No conflicts of interest.”
Manel Juan declares that he has no conflicts of interest other than knowing some of the authors, in no case at a financial level.
Josep Tabernero declares having personal financial interests in the form of scientific consultancy (none direct with the work) for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc. Actions: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER).