Promises and challenges of adoptive T-cell therapies for solid tumours

Abstract

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

Conflict of interest statement

J.D.B. has received honoraria from consulting/honoraria with AstraZeneca and GSK, receives research support from Aprea AB and holds equity in Inivata and Tailor Bio. T.D has received honoraria from consulting with Oxford Immunotec Limited. M.L.D. is a scientific advisory board member of Adaptimmune. N.M. has received consultancy fees and has stock options in Achilles Therapeutics. N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/ 059401), identifying patient response to immune checkpoint blockade (PCT/ EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221). M.L.M. has received honoraria from GSK which are not related to this work. L.W.S. is founder, consultant and holds equity in two oncolytic virus companies (Psioxus Therapeutics Ltd and Theolytics Ltd). C.Y. receives enumeration for consultancy for Singula Bio Ltd. D.N.C. is a scientific advisory board member of MSD. A.A.A. is a founder, shareholder and consultant for Singula Bio Ltd. M.M., As.A., Aa.A., M.A., S.M.C., Z.H., L.S.G., T.S., P.V.L., H.W. and N.W. declare no conflict of interest.

Figures

Fig. 1. Targeting cancer neoantigens using cell therapy.

a Using autologous tumour-infiltrating lymphocytes in autologous cell transfer. The resected specimen is divided into multiple tumour fragments that are individually grown in IL-2 for 7–10 days. For the ‘non-specific’ TIL therapy (dashed line) the individual cultures are then moved to a rapid expansion protocol before reinfusion into patients. Neoantigen-TIL therapy involves the sequencing of exomic or whole-genome DNA from tumour cells and healthy cells to identify tumour-specific mutations, before RNA-sequencing is used to check for the expression of mutations. Corresponding minigenes or peptides encoding each mutated amino acid are synthesised and expressed in or pulsed into a patient’s autologous antigen-presenting cells (APCs) for presentation in the context of a patient’s HLA. Individual mutations responsible for tumour recognition are identified by analysing activation of a T-cell co-stimulatory marker, such as 41BB/CD137 (CD8+ T cells), in response to cognate target antigen recognition. b Genetic and genomic heterogeneity and evolution of clonal populations. Upper panel: Genetic and phenotypic variations are observed between tumours of different tissues (inter-tumour heterogeneity). Within a tumour, subclonal diversity can be observed (intra-tumour heterogeneity, different colours of tumour clones). Clonal alterations occurring early in tumorigenesis are represented by the blue trunk of the phylogenetic tree (truncal mutations); later alterations could be shared by tumour cells in some regions of the tumour (light blue and pink branches of the tree) or present in only one region of the tumour (yellow branches of the tree) in a branched cancer evolution model. Tumour subclones can also show differential gene expression due to non-genetic heterogeneity. Lower row: Unique clones (represented by different colours) emerge as a consequence of accumulating driver mutations in the progeny of a single most recent common ancestor cell. Ongoing linear and branching evolution results in multiple simultaneous subclones that can individually give rise to episodes of disease relapse and metastasis. c Overview of the neoantigen landscape. The sources of potential neoantigens for HLA class I ligands are shown. In tumours, mutated or aberrantly expressed proteins are processed via the proteasome into peptides. The cross-priming abilities of peptides are also linked to non-genetic factors such as protein stability, which can be modulated by several factors, including their localisation in the mitochondria. These peptides can be loaded onto HLA class I molecules and might or might not elicit a CD8+ T-cell response, depending on several factors, including peptide sequence or T-cell receptor (TCR) sequences. In general, most of the neoantigens derived from single-nucleotide variants gain their immunogenicity through altered amino acids involved in direct T-cell contact.

Fig. 2. T cell conditioning to overcome the immunosuppressive tumour microenvironment.

a Immuno-evasion mechanisms in the tumour microenvironment. A representative example of an ‘excluded’ (cold) T-cell tumour is shown. Some of the most studied immune cells along with their ligand–receptor and secreted growth factors (chemokines and cytokines) known to promote immunoevasion are shown. In the black box, examples are given of cancer genetic alterations linked to an immuno-evasive tumour microenvironment (ADE adenosine, ARG1 Arginase 1, CAFs cancer-associated fibroblasts, DC dendritic cell, IL interleukin, iNOS inducible nitric oxide synthase, KYN: kynurenine, MDSC myeloid-derived suppressor cells, NO nitric oxide, PGE2 prostaglandin E2, ROS reactive oxygen species TAMs tumour-associated macrophages, TGF-β transforming growth factor-β, Treg regulatory T cell, VEGF vascular endothelial growth factor). In the black box are highlighted genetic mechanisms linked to a cold TME. b T cell exhaustion in solid tumours. A representative image of transitions from an effector (Teff) to an exhausted (Tex) T cell is shown. Chronic antigen exposure and the TME pressure promote the activity of transcription factors (such as NFAT, TOX), which increases the expression of exhaustion-associated molecules such as PD1, LAG3, and TIM3, and the downregulation of effector cytokines such as IFNγ, GrzB and IL-2 sensitivity. GrzB Granzyme B, IL2 interleukin-2, TME tumour microenvironment, TRM tissue-resident memory. c Potential interventions to increase TIL efficacy during the expansion of T cells for ACT. The tumour microenvironment (TME) can be modulated ex vivo with different drugs (such as epigenetics, immunometabolic drugs) or interleukins (e.g. IL-2, IL-15) to boost the growth and activation of tumour-infiltrating lymphocytes, to increase the number of neoantigens (epigenetic drugs) or to preferentially expand TIL-specific subtypes such as tissue resident memory T cells (TRM-TILs). CRISPR–Cas9 ribonuclear protein complexes loaded with single-guide RNAs can be electroporated into TILs or normal T cells for gene editing. Shown here is an example of deletion of TCRs (off-the-shelf T cells) and of inhibiting immune checkpoint receptors such as programmed death 1 (PD-1) in T cells. Protein engineering can be used for the creation of orthogonal IL-2–IL-2 receptor pairs, which consist of a mutant orthogonal IL-2 cytokine (oIL-2) and mutant IL-2 receptor (oIL-2R) that interact specifically with each other but do not interact with their wild-type counterparts. SMAPs (supramolecular attack particles) can be produced in vitro and grafted to relevant specific TCRs for adoptive transfer.

Fig. 3. ATMP manufacturing chain and challenges.

The chain starts with the cell-therapy team providing direct patient care. After apheresis or biopsy collection at the cell-therapy hospital, the material is anonymised, and the relevant setting is required to maintain a chain-of-custody tracking. The governance and administration team oversee the cell-therapy programme, the development and management of standard operating procedures, the outcomes of auditing processes as well as assess resource allocation and business planning. The biopsy sample is processed and transported to the manufacturing facility with a system to ensure that the integrity and chain-of-custody of the initial cellular material are maintained. At the manufacturing facility (centralised or decentralised), manufacturing specialists in GMP procedures with expertise in the standardisation of cell-therapy protocols are needed. Clean room requirements are determined by the use of open versus closed systems. A cell-product storage facility along with electronic database infrastructure for health record documentation and quality reporting preparation of manufactured products with a chain-of-custody are required. Transport of the cell product back to the hospital requires temperature and storage controls to maintain viability. In the hospital/organisation, a financial service dealing with single-case insurance agreements and institutional payer relations is required. A legal and compliance team overseeing the manufacturer contractual agreements, the interfaces with commercial manufacturers, as well as regulatory assessment for potential international trials, is also required. Similarly, staff education to provide proper clinical training and scientific and regulatory competencies (cell-therapy fellowships) are required.