The following text is written by Immunocore: Harnessing the power of T cells against cancer



Over the past two decades, significant advances have been made in immuno-oncology, but restrictions such as the reliance on antibody-based targeting of cell-surface proteins have limited the applicability of existing approaches. T cell receptor (TCR) therapy is a new branch of immuno-oncology that is able to overcome the limitation associated with antibody-based therapeutics by targeting intracellular antigens, in theory unlocking the entire proteome. Immunocore has innovated a novel form of T cell receptor technology, engineering and developing a modular molecule that combines a target-identifying TCR and an immune-activating effector function. The company launched the world's first bispecific TCR therapy in 2022, for metastatic uveal melanoma, and has trials ongoing in cutaneous melanoma.

Initiating an effective anti-cancer immune response is the central goal of cancer immuno-oncology. However, there are mechanisms of resistance that preclude immune recognition and include, but are not limited to, very low number of acquired mutations within the cancer cell, deletion or exhaustion of T cells capable of recognizing tumor antigens, an immuno-suppressive microenvironment around the tumor, and down-regulation of antigen presentation machinery. Cancer cells can also deactivate (or exhaust) cancer-specific T cells by overexpressing ligands for immune checkpoint receptors, such as CTLA4 and PD1 (Jiang, Li & Zhu, 2015). Checkpoint inhibitors like anti-CTLA4 and anti-PD1/-PDL1 antibodies can block these interactions, but their effects are limited if the tumor has a low mutational burden or there is an absence of pre-existing tumor-specific T cells (Morad et al., 2021).     Redirecting T cells can potentially bypass the absence or exhaustion of tumor-specific T cells regardless of their intrinsic (or natural) specificity and can be achieved by chimeric antigen receptor T cells (CAR-T cells) or bispecific antibody-based T cell engagers (Barrett et al., 2014; Laskowski & Rezvani, 2020). However, all antibody-targeted recognition of tumor cells has the limitation of only recognizing proteins presented on the cell surface. This presents a challenge for the treatment of solid tumors due to the limited number of cancer-specific antigens on the cell surface, which also tend to be present in low numbers (Lowe et al., 2019; Berman & Bell, 2022). Therefore, finding new cancer-specific intracellular antigens and approaches to target them is a major hurdle for cancer immunotherapy.   In contrast to antibodies, T cell receptors (TCRs) can specifically recognise intracellular proteins as processed peptides bound to human leukocyte antigen (HLA) proteins presented on the cell surface. A new class of bispecific biologics called immune mobilising monoclonal TCRs against cancer (ImmTAC), has the potential to recognize >90% of the proteome, including intracellular proteins, with high sensitivity to as few as 10 peptide-HLA complexes per cell (Liddy et al., 2012). ImmTAC molecules are soluble bispecific fusion proteins, comprised of an affinity-enhanced TCR fused to an antibody fragment targeting CD3 (cluster of differentiation 3). The TCR arm recognizes and binds with high affinity and specificity to a peptide presented in the context of an HLA molecule on the cell surface of tumor cells. The effector arm binds to CD3, an activating receptor expressed on the surface of all T cells, resulting in redirection and activation of T cells regardless of their native TCR specificity. Once activated, T cells release inflammatory cytokines and chemokines that stimulate the local immune response and cytolytic proteins for direct killing of tumor cells (Damato et al., 2019).

Compared to a natural TCR, the highly engineered TCR arm of an ImmTAC molecule has a 106-fold increased affinity for its target peptide-HLA complex. In contrast to the TCR arm, the anti-CD3 arm is designed to bind CD3 with a 1000-fold lower affinity. This differential affinity allows the ImmTAC to stay bound to the target for a sufficient time, while ImmTAC-redirected T cells can disengage and re-engage multiple times (i.e., serial triggering) (Berman & Bell, 2022). In addition to cytotoxic CD8+ cells, ImmTAC molecules can activate other T cell subsets including CD4+ T cells, which can enhance cytotoxic CD8+ T effector functions and protect the cells from exhaustion (Boudousquie et al., 2017).   Given all T cell receptors are restricted to a specific allelic variant of HLA, ImmTAC molecules are similarly restricted to a single allelic variant of the HLA, currently limited to A*02:01 (Damato et al., 2019; González-Galarza et al., 2015). Research is ongoing to develop new ImmTAC molecules targeting additional HLA alleles as well as pursuing strategies to overcome HLA restriction altogether.   Tebentafusp (IMCgp100) was the first ImmTAC molecule to enter the clinic and to be subsequently approved for the treatment of adult patients with HLA-A*02:01+ with unresectable or metastatic uveal melanoma. Tebentafusp recognises a peptide derived from the melanocyte lineage specific antigen gp100 (gp100280-288) in complex with HLA-A*02:01. Gp100 is expressed in melanocytes and overexpressed in melanoma. To date, tebentafusp was evaluated in phase I/II (IMCgp100-102) and phase III (IMCgp100-202) clinical trials for treatment of metastatic uveal melanoma. Additionally, tebentafusp is being investigated as either monotherapy or in combination with pembrolizumab in a global randomized phase II/III trial in patients with advanced cutaneous melanoma (IMCgp100-203; NCT05549297).   With the approval of tebentafusp across more than 30 countries, Immunocore is the only commercial-stage TCR company in the world and is pioneering the development of off-the-shelf soluble TCR bispecific fusion proteins. With multiple clinical-stage programs in development, Immunocore is keen to engage with healthcare professionals who want to learn more about our novel platform technology, take part in our sponsored clinical trials, as well as explore potential scientific collaborations to understand better the potential applications of the ImmTAC platform.     References:   Barrett DM, Grupp SA, June CH. Chimeric Antigen Receptor- and TCR-Modified T Cells Enter Main Street and Wall Street. J Immunol. 2015 Aug 1;195(3):755-61. doi: 10.4049/jimmunol.1500751. PMID: 26188068; PMCID: PMC4507286. Berman DM, Bell JI. Redirecting Polyclonal T cells Against Cancer with Soluble T Cell Receptors. Clin Cancer Res. 2022 Oct 18:CCR-22-0028. doi: 10.1158/1078-0432.CCR-22-0028. Epub ahead of print. PMID: 36255733. Boudousquie C, Bossi G, Hurst JM, Rygiel KA, Jakobsen BK, Hassan NJ. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells. Immunology. 2017 Nov;152(3):425-438. doi: 10.1111/imm.12779. Epub 2017 Aug 2. PMID: 28640942; PMCID: PMC5629433. Damato BE, Dukes J, Goodall H, Carvajal RD. Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma. Cancers (Basel). 2019 Jul 11;11(7):971. doi: 10.3390/cancers11070971. PMID: 31336704; PMCID: PMC6679206. González-Galarza FF, Takeshita LY, Santos EJ, Kempson F, Maia MH, da Silva AL, Teles e Silva AL, Ghattaoraya GS, Alfirevic A, Jones AR, Middleton D. Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations. Nucleic Acids Res. 2015 Jan;43(Database issue):D784-8. doi: 10.1093/nar/gku1166. Epub 2014 Nov 20.PMID: 25414323; PMCID: PMC4383964. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015 Jun 18;6(6):e1792. doi: 10.1038/cddis.2015.162. PMID: 26086965; PMCID: PMC4669840. Laskowski T, Rezvani K. Adoptive cell therapy: Living drugs against cancer. J Exp Med. 2020 Dec 7;217(12):e20200377. doi: 10.1084/jem.20200377. PMID: 33227136; PMCID: PMC7686916. Liddy N, Bossi G, Adams KJ, Lissina A, Mahon TM, Hassan NJ, Gavarret J, Bianchi FC, Pumphrey NJ, Ladell K, Gostick E, Sewell AK, Lissin NM, Harwood NE, Molloy PE, Li Y, Cameron BJ, Sami M, Baston EE, Todorov PT, Paston SJ, Dennis RE, Harper JV, Dunn SM, Ashfield R, Johnson A, McGrath Y, Plesa G, June CH, Kalos M, Price DA, Vuidepot A, Williams DD, Sutton DH, Jakobsen BK. Monoclonal TCR-redirected tumor cell killing. Nat Med. 2012 Jun;18(6):980-7. doi: 10.1038/nm.2764. PMID: 22561687. Lowe KL, Cole D, Kenefeck R, OKelly I, Lepore M, Jakobsen BK. Novel TCR-based biologics: mobilising T cells to warm 'cold' tumours. Cancer Treat Rev. 2019 Jul;77:35-43. doi: 10.1016/j.ctrv.2019.06.001. Epub 2019 Jun 12. PMID: 31207478. Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2022 Feb 3;185(3):576. doi: 10.1016/j.cell.2022.01.008. Erratum for: Cell. 2021 Oct 14;184(21):5309-5337. PMID: 35120665. Oates J, Hassan NJ, Jakobsen BK. ImmTACs for targeted cancer therapy: Why, what, how, and which. Mol Immunol. 2015 Oct;67(2 Pt A):67-74. doi: 10.1016/j.molimm.2015.01.024. Epub 2015 Feb 21. PMID: 25708206. Robinson J, Barker DJ, Georgiou X, Cooper MA, Flicek P, Marsh SGE. IPD-IMGT/HLA Database. Nucleic Acids Res. 2020 Jan 8;48(D1):D948-D955. doi: 10.1093/nar/gkz950. PMID: 31667505; PMCID: PMC7145640. Robinson RA, McMurran C, McCully ML, Cole DK. Engineering soluble T-cell receptors for therapy. FEBS J. 2021 Nov;288(21):6159-6173. doi: 10.1111/febs.15780. Epub 2021 Mar 10. PMID: 33624424; PMCID: PMC8596704.

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