Although T cells genetically modified with chimeric antigen receptors became the first immune effector product to obtain FDA approval, T-cell products that recognize their antigenic targets through their native receptors have also produced encouraging responses. For instance, T cells recognizing immunogenic viral antigens are effective when infused in immunosuppressed patients. A large number of tumor antigens are also expressed on non-viral tumors, but these antigens are less immunogenic. Many tumors can evade a transferred immune response by producing variants, which have lost the targeted antigens, or inhibitory molecules that recruit suppressive cells, impeding persistence and function of immune effectors. Nevertheless, infusion of antigen-specific T cells has been well-tolerated, and clinical responses have been consistently associated with immune activity against tumor antigens and epitope spreading. In order to overcome some of the obstacles mentioned above, current research is focused on defining ex vivo culture conditions that promote in vivo persistence and activity of infused antigen-specific T cells. Combinations with immune checkpoint inhibitors or epigenetic modifiers to improve T-cell activity are also being evaluated in the clinic. Antigen-specific T cells may also be manufactured to overcome tumor evasion mechanisms by targeting multiple antigens and engineered to be resistant to inhibitory factors such as TGFβ or to produce the cytokines that are essential for T-cell expansion and sustained antitumor activity. Here, we discuss the use of T cells specific to tumor antigens through their native receptors and strategies under investigation to improve antitumor responses.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for relapsed or refractory acute myeloid leukemia (AML). However, more than half ultimately experience disease relapse that is associated with a dismal median survival of just 6 months, highlighting the need for novel therapies. In the current study we explore the therapeutic potential of targeting cyclin A1 (CCNA1), a cancer-testis antigen that is overexpressed in malignant blasts and leukemic stem cells. We demonstrate the immunogenicity of this antigen to native T cells, with >90% of donors screened mounting a specific response. The expanded cells were Th1 polarized, polyfunctional, and cytotoxic toward CCNA1+/HLA-matched tumor cell lines. Furthermore, these cells were exquisitely specific for CCNA1 and exhibited no reactivity against other cyclin family members, including CCNA2, which shares 56% homology with CCNA1 and is ubiquitously expressed in dividing cells. Lastly, the detection of CCNA1-specific T cells in AML patients post-HSCT was associated with prolonged disease remission, suggesting the protective potential of such endogenous cells. Taken together, our findings demonstrate the feasibility of targeting CCNA1 and the potential for therapeutic benefit associated with the adoptive transfer of reactive cells.
A lower frequency of the favorable prognostic marker ETV6-RUNX1 was observed in Maori pediatric ALL patients. This did not translate into poorer survival. Future research into biological and nonbiological prognostic factors in this patient population may assist in explaining this finding.
Purpose: Adoptively transferred, ex vivo expanded multi-antigen-targeted T cells (multiTAA-T) represent a new, potentially effective, and nontoxic therapeutic approach for patients with breast cancer (BC). In this first-in-human trial, we investigated the safety and clinical effects of administering multiTAA T cells targeting the tumor-expressed antigens, Survivin, NY-ESO-1, MAGE-A4, SSX2, and PRAME, to patients with relapsed/refractory/metastatic BC. Materials and methods: MultiTAA T-cell products were generated from the peripheral blood of heavily pre-treated patients with metastatic or locally recurrent unresectable BC of all subtypes and infused at a fixed dose level of 2 × 107/m2. Patients received two infusions of cells 4 weeks apart and safety and clinical activity were determined. Cells were administered in an outpatient setting and without prior lymphodepleting chemotherapy. Results: All patients had estrogen receptor/progesterone receptor positive BC, with one patient also having human epidermal growth factor receptor 2-positive. There were no treatment-related toxicities and the infusions were well tolerated. Of the 10 heavily pre-treated patients enrolled and infused with multiTAA T cells, nine had disease progression while one patient with 10 lines of prior therapies experienced prolonged (5 months) disease stabilization that was associated with the in vivo expansion and persistence of T cells directed against the targeted antigens. Furthermore, antigen spreading and the endogenous activation of T cells directed against a spectrum of non-targeted tumor antigens were observed in 7/10 patients post-multiTAA infusion. Conclusion: MultiTAA T cells were well tolerated and induced disease stabilization in a patient with refractory BC. This was associated with in vivo T-cell expansion, persistence, and antigen spreading. Future directions of this approach may include additional strategies to enhance the therapeutic benefit of multiTAA T cells in patients with BC.
T cell receptor engineered T cell (TCR T) therapy has emerged as a promising therapeutic modality for solid cancer following recent trials demonstrating the safety and efficacy of TCR T therapies against some types of metastatic solid cancers. However, the broader application of TCR T towards many solid tumors, including metastatic breast cancer (MBC), has been limited by several factors, chiefly among them the current scarcity of tumor selective target antigens. Neoantigens, which are expressed exclusively in cancer cells, are currently underrepresented in TCR T development, being targeted in only about 7% of trials conducted to date, and thus represent a relatively untapped source of potentially safe and effective novel targets. Driver mutations in AKT1, ESR1, PIK3CA, and TP53 are common in patients with MBC, and could serve as ideal neoantigen targets for TCR T therapies. We hypothesized that we could generate MBC driver mutation-specific T cells from which we could isolate and clone neoantigen-specific TCRs to generate TCR T products for MBC. We identified 13 driver missense mutations that are among the most frequent in patients with MBC, which included AKT1 (E17K), ESR1 (K303R, Y537S, D538G), PIK3CA (E542K, E545K, H1047L, H1047R), and TP53 (R175H, R248Q, R248W, R273C, R273H), then designed peptide libraries consisting of 15-mer overlapping peptides that contain these mutations. To determine if these neopeptides could elicit T cell responses, we isolated T cells from 15 healthy donors and 11 MBC patients who expressed at least one of the targeted mutations and performed successive stimulations with neopeptide pulsed dendritic cells, then screened the resulting T cell lines for neoantigen specificity using an IFN-γ ELISpot assay. We observed neopeptide T cell responses in 8/16 lines generated from healthy donors and 7/11 lines generated from MBC patients, which were collectively directed against 11/13 of the targeted driver mutations. To isolate neoantigen-specific TCRs from one of these lines, we performed IFN-γ capture, limiting dilution, and 5’ RACE, and isolated an HLA-B*35 restricted TP53 R248W-specifc TCR. Gene transfer of this TCR conferred edited T cells with potent activity towards the TP53 R248W and not the TP53 WT peptide as assessed by ELISpot (1036 vs 46 SFU/1 × 105 cells, respectively) and chromium release cytoxicity assay targeting peptide pulsed autologous PHA blasts (37.5% vs 0% lysis at E:T 40:1, respectively). To increase the throughput of TCR discovery, we next used a single cell RNA sequencing based TCR discovery approach whereby we stimulated T cells from one of the generated lines with ESR1 WT or neopeptide and identified responsive T cell clones through upregulation of IFN-γ and/or TNF-α. This strategy has so far enabled us to identify and validate two ESR1 mutant-specific TCRs. This includes an HLA-C*01 restricted TCR that confers edited T cells with dual activity towards both ESR1 Y537S and D538G, but not WT peptide as determined by both ELISpot (2094, 3194, and 79 SFU, respectively) and chromium release cytotoxicity (31.3%, 77.8%, and 9.1% lysis, respectively), as well as an HLA-B*40 restricted TCR that confers high ESR1 Y537S specificity (5039 vs 138 SFU in response to ESR1 Y537S vs WT peptide, respectively). In summary, we have demonstrated responses of T cells derived from both healthy donors and MBC patients towards neopeptides derived from common MBC driver mutations. We have so far isolated neoantigen specific TCRs from two of the neoantigen-specific T cells lines, including TCRs specific towards TP53 R248W, ESR1 Y537S, dual ESR1 Y537S+D538G that are restricted to three different HLA alleles, and have successfully used these TCRs to generate TCR T products with high neoantigen activity. These results encourage further efforts to identify TCRs recognizing these MBC driver mutations, with our ultimate aim to translate neoantigen-targeted TCR T therapies to clinical trials of MBC. Citation Format: Paul Shafer, Wingchi K. Leung, Mae L. Woods, Carlos Rodriguez-Plata, Arushana Ali, Saisha Nalawade, Lauren M. Kelley, Jarrett Joubert, Anthony Manliguez, Spyridoula Vasileiou, Suzanne A. Fuqua, Premal Lulla, Cliona Rooney, Ann Leen, Valentina Hoyos. Engineered neoantigen-specific T cell receptors to treat metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-11.
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