Antigen-specific T cells have been used as cancer therapies by targeting (i) viral peptides in virus-associated malignancies, (ii) germline antigens that have limited expression on normal tissues (e.g., cancer testis antigens [CTAs]), and (iii) cancer mutation derived neoantigens. We summarize the clinical outcomes of selected clinical trials using unmodified antigen-specific T-cell immunotherapy in Table1.

Table1. Selected Published Studies Using Tumor-Specific T Cells (Through TCR) for Cancer

Table1. Selected Published Studies Using Tumor-Specific T Cells (Through TCR) for Cancer —cont’d

Adoptive Immunotherapy of Virus-Associated Malignancies

 Viruses cause approximately 12% of cancers. These cancers express viral oncoproteins that can serve as targets for adoptive cell therapy. Early successes with adoptive immunotherapy with EBV–VSTs as prophylaxis and treatment of post-transplant LPD, which arises in immunocompromised patients, led to the extension of this strategy to other EBV+ tumors (lymphoma and nasopharyngeal cancer) that develop in immunocompetent patients. Unlike EBV-LPD, which expresses a diverse array of viral latency antigens, including the highly immunogenic EBNA3 and EBNA2, other EBV+ tumors are less immunogenic and express few poorly processed (EBNA1) or weakly stimulatory (latent membrane protein: LMP1 and LMP2) EBV-derived antigens. Nevertheless, infusion of polyclonal LMP2 specific CD4+ and CD8+ T cells or CD8+ LMP2-specific T cells (restricted to HLA-A2 and A24 only) increased EBV peptide-specific T-cell responses and led to sustained complete tumor regression in patients with a diverse array of relapsed/resistant EBV+ lymphoma. A multicenter cooperative group phase III clinical trial is ongoing to assess the efficacy of autologous EBV-specific T cells for the treatment of refractory EBV+ lymphomas.

In order to increase the antitumor activity of EBV-directed T cells, a separate trial infused EBV-specific T cells genetically engineered to overcome transforming growth factor-β (TGFβ)-mediated T-cell inhibition to seven patients with EBV+ lymphomas. Of these, four had a sustained response with persisting LMP-specific T cells for more than 4 years following infusion. Thus, genetic modifications of these cells appear safe and may be necessary to overcome the suppressive tumor microenvironment and increase T-cell activity in immunocompetent patients.

Adoptive Immunotherapy of Virus-Independent Malignancies

For malignancies not associated with viruses, T cells must target alternative antigens to achieve clinical responses. A wide variety of germline “tumor-associated antigens (TAAs)” or mutated “neo antigens” are suitable T-cell targets due to qualities such as tumor exclusive expression or overexpression, T-cell immunogenicity, and the association between endogenous responses to these antigens and clinical outcomes. Compared to VSTs, manufacturing TAA specific T cells is limited by physiologic and pathologic barriers. Physiologically, the vast majority of T cells with high affinity for self-antigens are deleted during T-cell development, while those that persist are frequently anergic because of the highly immunosuppressive tumor environment. Thus, ex vivo expansion strategies using single peptide/antigen expressing stimulator cells in culture result in considerable variability in the anti-tumor function of manufactured products. To overcome this limitation, investigators have taken the approach to (i) harvest tumor infiltrating lymphocytes (TILs) that have been shown to be enriched for TAA-reactive T cells and expand them non-specifically; (ii) stimulate and expand T cells with specificity for not just single but multiple TAAs, thereby improving the chances of manufacturing a product with antitumor function coupled with broader targeting to address tumor heterogeneity; or (iii) transduce T cells with peptide-specific T-cell receptors (TCRs).

In the clinic, adoptive T-cell approaches have centered on targeting neoantigens or two major sources of non-mutated, non-viral antigens expressed by tumor cells: (1) Mismatched histocompatibility antigens and (2) “cancer-testis” or equivalent antigens, where target peptides are sufficiently foreign to elicit robust T-cell responses.

Neoantigens

Neoantigens are novel protein sequences arising from non-synonymous mutations in malignant cells that can be presented by HLA to induce an anti-tumor immune response. Neoantigens arise from translocations (e.g., BCR-ABL1 t(9;22)), point mutations (e.g., KRAS G12D), or insertions/deletions and lead to an alternate reading frame and consequently a novel peptide, rendering them attractive immunotherapeutic targets due to their restricted expression. Furthermore, as neoantigens are considered “foreign,” cognate T cells clones are likely spared from negative thymic selection, thereby allowing persistence of high affinity TCRs that have enhanced activation and cytotoxicity.

Determining immunogenic antigens and their major histocompatibility complex (MHC) restriction remains challenging but is crucial to developing efficacious neoantigen-directed immunotherapies. Pioneering work by Rosenberg et al. demonstrated the presence of neoantigen-specific T cells that mediate complete responses in patients with a variety of solid tumors (e.g., colon cancer, cholangiocarcinoma, melanoma, breast cancer, etc.) in expanded TILs. The discovery that relapses following TIL therapy can be attributable to loss of neopeptide presentation is further proof of their immune effect on tumors. Vaccination offers an alternative strategy to target neoantigens. While therapy with TILs is a form of passive immunity which involves the adoptive transfer of ex vivo expanded tumor-directed T cells, vaccinations stimulate activity immunity in endogenous T cells for anti-tumor activity and has been tested in phase I clinical trials for melanoma and glioblastoma. Recent advances in high-throughput genome sequencing uncovered an increasing list of tumor mutations that may encode for neoantigens presented by MHC molecules. While in silico algorithms can predict clinically relevant, neoepitope: MHC complexes based on the mutated sequences, mass spectrometry approaches that immunoprecipitate MHC complexes with their peptides are currently being used to design personalized neoantigen targeted immunotherapies, as these techniques can directly identify candidate neoantigens, including those that are modified during translation/transcription of the mutated sequences. In Table 1, we describe clinical activity of published reports of neoantigen-specific T cells used as cancer immunotherapy.

Mismatched Histocompatibility Antigens

In the allogeneic setting, alloreactivity toward mismatched major or minor histocompatibility antigens (miHA) on recipient tissues are a major source of non-mutated target antigens driving both GVT and GVHD. In a pivotal report, Warren et al. administered donor T lymphocytes that were reactive to a range of recipient expressed miHAs and observed both on-target GVT as well as on-target but off tumor pulmonary toxicity. Since then, the focus of targeting miHAs has shifted to those that have natural target-tissue specific expression (e.g., histocompatibility antigen 1 [HA-1] that is expressed only on hematopoietic tissues and hematologic malignancies) and are thus less likely to induce reactions in normal non-target tissues.

Non-Histocompatibility, Germline Antigens

Outside of mismatched histocompatibility antigens, “cancer-testis” antigens represent the major source of germline-derived target antigens for T-cell immunotherapy. Most CTAs (e.g., NYESO1, MAGE) were discovered by studying the target antigen profile of TILs. These anti gens are selectively overexpressed by tumor cells with normal expression restricted to immune-privileged gonadal tissues. Thus, T lymphocytes with specificities for CTAs may not be deleted by the mature thymus during central tolerance. Though not true of CTAs, a number of anti gens have been discovered that have limited normal tissue expression but are overexpressed by cancer cells by virtue of altered epigenetics (e.g., WT1) or rapid cell cycling (e.g., Cyclin A1, Survivin).

As an extension of TIL therapy in solid tumors, Noonan et al. treated myeloma patients with analogous “marrow-infiltrating lymphocytes” or MILs.

Since TILs or MILs are not always available and have considerable variability in quality and quantity among patients, another approach is to expand TAA-reactive T cells from the periphery by stimulating with TAAs ex vivo. In this regard, our group and others have demonstrated the clinical safety of administering expanded T cells with natural TAA reactivity to patients with a variety of refractory cancers. These mostly small cohort studies target TAAs that are predicted or known to be expressed by tumor cells, and the products manufactured target single or multiple TAAs simultaneously (see Table 1). While encouraging efficacy has been demonstrated in these reports, larger, multi-institutional, efficacy-based trials are ongoing.

Other groups have transduced T cells with artificial TCRs with defined specificity for single peptides derived from a TAA. Notably, in their proof-of-principle clinical trial, Rappaport et al. demonstrated the safety of targeting a peptide derived from NYESO1/LAGE1 in patients with myeloma and sarcomas. In this trial, these T cells substantially improved progression-free survival in patients (15 of 20 remained in remission for over 1 year). The authors also observed loss of the target antigen in relapsing tumors as a mechanism of immune escape. Similarly, two groups demonstrated leukemia-directed efficacy without GVHD of engineering donor-T cells to express WT1 peptide specific TCRs in patients with AML.

Targeting germline antigens with artificial, affinity enhanced TCRs carries the risk for self-reactivity. Indeed, in two patients who received T cells transduced with a TCR specific for a peptide derived from the TAA MAGE-A3 had cardiac toxicity that led to death. An elegant investigation demonstrated that the transduced TCR was “codon-optimized,” resulting in high level avidity and affinity for the MAGE-A3 peptide, but also a peptide from titin, which is an unrelated germline antigen, highly expressed by normal cardiac myocytes.

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مواضيع ذات صلة

Clinical Results of Chimeric Antigen Receptor T Cells in Hematologic Malignancies

Types of Cellular Immunotherapy

Therapeutic Manipulation of T-Cell-Mediated Immunity

T-Cell Exhaustion: Impaired Response after Chronic Antigen Exposure

T-Cell Memory

Regulatory T Cells

T-Cell Function

The T-Cell Receptor Complex

Antigen Presentation: Creating the Ligand for the T-Cell Receptor

Therapeutic Passive Immunization and Monoclonal Antibody Therapy

Adverse Events Related to Intravenous Immunoglobulin Infusion

Therapeutic use of Immunoglobulin : Intravenous Immunoglobulin