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Unmodified Ex Vivo Expanded T Cells
T lymphocytes have the natural ability to destroy viral-infected or tumor target cells by a range of mechanisms that are initiated upon recognition of target peptides presented by histocompatibility antigens. Coupled with their ability to traffic through multiple tissues and self-renew, these properties make T lymphocytes an appealing cell-type for adoptive immunotherapy of cancer. Allogeneic hematopoietic stem cell transplantation (HSCT) is enduring “proof-of-principle” for adoptive immunotherapy with unmodified T cells. The introduction into an allogeneic recipient of an unselected donor T-cell repertoire by HSCT or through donor lymphocyte infusions (DLIs) induces a potent “graft-versus-tumor (GvT)” immune effect that can cure patients of their primary malignancy. However, this effect is non-specific and is frequently accompanied by life threatening “graft-versus-host disease (GVHD).” Additionally, as our understanding of the molecular basis of immunotherapy has increased, we have uncovered many pathways of tumor-mediated immune evasion that must be overcome for T cell-based immunotherapies to be curative.
In this chapter, we review ongoing efforts to refine the antigen-specificity of adoptively transferred unmodified T cells ( Fig. 25.1 ), as well as strategies to overcome tumor-mediated inhibition of immunotherapy with these T cells ( Fig. 25.2 ).
TYPES OF NON-CAR-BASED ADOPTIVE T-CELL THERAPY.
(1) Antigen agnostic approaches. Donor lymphocyte infusions (DLI), hematopoietic stem cell transplantation (HSCT), tumor infiltrating lymphocytes (TIL) or marrow infiltrating lymphocytes (MIL) . (2) Antigen-driven selection of reactive T cells. (3) Antigen-driven ex vivo expansion of reactive T cells. (4) Transduction of an artificial, antigen-reactive T cell receptor (TCR).
EMERGING CHALLENGES TO ADOPTIVE T-CELL IMMUNOTHERAPY.
(1) Immunoediting of target-antigen presentation. (2) Overexpression of immune checkpoints. (3) Proliferation of regulatory T cells (Tregs). (4) Proliferation of myeloid derived suppressor cells (MDSCs). (5) Immunosuppressive factors within the tumor microenvironment (e.g., stromal cells, transforming growth factor-β [TGFβ], indoleamine 2,3-dioxygenase [IDO], etc.). MHC , Major histocompatibility complex; TCR , T-cell receptors.
Adoptive Immunotherapy of Viral Infections with Virus-Specific T Cells
Viral infections with latent (e.g., cytomegalovirus [CMV], Epstein–Barr virus [EBV], BK virus [BKV]) and community-acquired respiratory viruses cause substantial morbidity and mortality in the HSCT setting. Since antiviral drugs are not always effective, investigators found that adoptive transfer of virus-specific T cells (VSTs) derived from the original stem cell donor, or more recently from “third-party” allogeneic donors, can control these infections ( Table 25.1 ).
Table 25.1
Selected Published Studies Using Allogeneic Unmodified Virus-Specific T Cells for Viral Infections
| Publication | Target | N | Donor | Safety | Response |
|---|---|---|---|---|---|
| Selection | |||||
| Cobbolt (2005)-Tetramer | CMV | 9 | Donor derived | 0 | 8 CR |
| Uhlin (2012)-Pentamer |
|
|
Donor derived, Third party | 0 |
|
| Neuenhahn (2017)-Streptamer | CMV | 16 | Donor derived, Third party |
|
9 CR |
| Feuchtinger (2006)-IFNγ capture | ADV | 9 | Donor derived | 1 GVHD | 4 CR |
| Moosman (2010)- IFNγ capture | EBV | 6 | Donor derived | 0 | 3 CR |
| Peggs (2011)-IFNγ capture | CMV | 18 | Donor derived | 8 GVHD |
|
| Kallay (2017)-IFNγ capture |
|
|
Third party | 1 CRS |
|
| Ex Vivo Expansion | |||||
| Walter et al. (1995) | CMV | 14 | Donor derived | 7 GVHD | Prophylaxis |
| Heslop (2010) | EBV | 114 | Donor derived |
|
|
| Leen (2006) |
|
|
Donor derived | 0 |
|
| Doubrovina (2012) | EBV | 19 | Donor derived, Third party | 0 | 13 CR |
| Papadopoulou (2014) |
|
|
Donor derived | 0 |
|
| Haque (2007) | EBV | 2 | Third party | 0 | 2 CR |
| Vickers (2014) | EBV | 11 | Third party | 1 aGVHD | 8 CR |
| Leen (2013) |
|
|
Third party | 8 aGVHD |
|
| Tzannou (2017) |
|
|
Third party |
|
|
| Prockop (2020) | EBV | 33 | Third party | 1 aGVHD | 19 CR |
ADV, Adenovirus; BKV, BK virus; CCR, continue response; CMV, cytomegalovirus; CR, complete response; CRS, cytokine release syndrome; EBV, Ebstein–Barr virus; GVHD, graft-versus-host disease (a = acute, c = chronic); HHV6, human herpes virus-6; N, sample size; NR, no response; PR, partial response; prophy, prophylaxis; Treat, cells administrated for treatment.
Methods to Generate Virus-Specific T Cells
Rapid Selection
Two rapid selection approaches to generate VSTs have been clinically tested to date. In the first approach, multimers are used to capture epitope-specific memory T cells from donors, while in the second donor T cells that secrete interferon gamma (IFNγ) or express activation markers like 4-1BB after exposure to viral antigens are captured using magnetic beads. The former strategy has been successful in controlling CMV, EBV, and adenoviral (ADV) infections without inducing toxicities, but it selects a monoclonal CD8+ population and is limited to specific human leukocyte antigen (HLA)-haplotypes and epitopes. By contrast, the second approach selects both CD4+ and CD8+ presumably multi-epitope VSTs and also demonstrated efficacy in controlling CMV, EBV, BKV and ADV reactivations post-HSCT. The CliniMACS Prodigy Cytokine Capture System, a closed system for IFNγ selection, was used to generate third-party VSTs that were infused in nine pediatric patients with CMV, EBV, and ADV infections. Seven of these patients achieved a complete response and only one experienced manageable toxicity in the form of mild cytokine release syndrome (CRS). A key limitation of both rapid-selection strategies is the requirement of large volumes of blood (usually a leukapheresis product) from which a relatively small number of VSTs can be isolated, sufficient for only one dose.
Ex Vivo Expansion
To overcome the small cell numbers generated by rapid selection, investigators have explored expanding VSTs ex vivo by stimulating them with engineered antigen-presenting cells (APCs) that express viral peptides or EBV-transformed lymphoblastoid cell lines (LCLs). Pioneering work from Fred Hutchinson Cancer Research Center and St. Jude Children’s Research Hospital demonstrated the feasibility of this method. Investigators prepared CMV- and EBV-reactive T cells, respectively, for clinical use and found them effective as prophylaxis and treatment of active infections. However, the manufacturing process was laborious, requiring prolonged cultures over multiple weeks. Efforts have since focused on simplifying manufacture, leading to the development of a 10-day process where clinical grade VSTs are generated by peptide library stimulation and peripheral blood mononuclear cells (PBMCs) serve as APCs. These rapidly expanded VSTs simultaneously targeting EBV, CMV, ADV, BKV, and human herpes virus-6 (HHV6) produced a 94% response rate without any increase in toxicity in a phase I study at Baylor College of Medicine.
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