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412 Part V: Therapeutic Principles Chapter 26: Immune Cell Therapy 413

EBV-specific T cells safely reconstituted immunity, mediated antiviral TABLE 26–1. Categories of Tumor Antigens
activity, and protected the majority of patients from EBV-LPD.
A. Classes of antigens for MHC-restricted T cells
MULTISPECIFIC T-CELL THERAPY OF VIRAL • Antigens arising from mutations or gene rearrangements (e.g.,
CDK-4, BCR/ABL)
INFECTIONS • Tissue-specific differentiation antigens (e.g., Tyrosinase, gp100)
Severe infections with a broad array of viruses remain a serious problem • Cancer-testes antigens (e.g., MAGE-1, NY-ESO-1)
for immunocompromised patients. 2–5,7,69 In addition to CMV and EBV, • Nonmutated overexpressed self-proteins (e.g., Her2/neu, WT-1)
infections with adenovirus, BK virus, human herpes virus-6 (HHV-6),
herpes simplex virus (HSV), and/or varicella-zoster virus can pose a • Oncofetal antigens (e.g., CEA)
serious problem. Antiviral drugs may benefit a subset of patients, but • Viral proteins in virus associated malignancies (e.g., HPV E6 and
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the effects are often limited and accompanied by toxicities. There is E7, EBV LMP-1)
inferential evidence that restoration of T-cell immunity is also criti- B. Classes of tumor cell surface molecules for chimeric antigen
cal for protection against these infections, suggesting that multivirus- receptor-modified T cells
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specific T-cell products would have greater utility. EBV-LCLs that
had been transfected with a recombinant adenovirus that encoded • B-cell differentiation molecules (e.g., CD19, CD20, CD22)
CMVpp65 were used to stimulate donor-derived PBMC and simultane- • Myeloid differentiation molecules (e.g., CD123)
ously expand T cells specific for adenovirus, CMV, and EBV. 31,72,73 The • Adhesion molecules (e.g., CD44v6, GD2, L1 CAM, mesothelin)
infusion of such multispecific T cells into HSCT recipients augmented • Oncofetal antigens (e.g., ROR1)
T-cell responses to all three viruses and promoted virus clearance. These • Signaling molecules (e.g., Her-2)
initial reports of adoptive T-cell therapy with “broad-spectrum” T cells • Hypoxia induced (e.g., CAIX)
to treat the multiplicity of distinct viral infections that may complicate
the clinical outcome of HSCT are encouraging. Studies have further
extended this work and demonstrated the feasibility and clinical utility
of rapidly generated T-cell lines that recognize 12 immunogenic anti- tumor-associated antigens, or chimeric antigen receptor (CAR)
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gens from five viruses, including CMV, EBV, adenovirus, BK virus, and genes that encodes a single chain mAb domain linked to the CD3ζ
HHV-6. Adoptive transfer of these T cells to 11 allogeneic transplant chain of the TCR, and confers recognition of a tumor-associated, cell-
recipients produced a greater than 90 percent sustained virologic and surface molecule, is facilitating the broader application of T-cell ther-
clinical response. 74 apy for both human hematologic malignancies and common epithelial
cancers. 94–97
ADOPTIVE CELLULAR THERAPY
OF MALIGNANCY CELLULAR THERAPY OF MELANOMA
Early studies demonstrated that the adoptive transfer of autolo-
There is evidence from murine models that the host immune system gous polyclonal tumor-infiltrating lymphocytes (TILs), isolated and
has a dynamic relationship with a developing tumor and can recognize, expanded from resected melanoma specimens, combined with the
control, and even eliminate cancer. 75–77 Immunogenic proteins in human administration of high-dose IL-2 resulted in a 31 percent response
tumors have now been identified by screening of tumor complementary rate in patients with advanced melanoma. Most of the responses
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DNA (cDNA) libraries with tumor-specific T cells isolated from the were transient, but these results validated the potential to eradicate a
blood or tumor environment, or by screening of patient sera for anti- human solid tumor with immunotherapy. These results also encour-
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body responses to tumor-associated proteins. Distinct categories of aged efforts to define the antigens recognized by TILs in responding
tumor antigens have been uncovered, and several are being investigated patients, and to refine the approaches to augmenting T-cell responses
as targets for T-cell therapy or vaccination (Table 26–1). However, the to tumor antigens.
clinical translation of adoptive T-cell therapy and other immunothera-
peutic modalities for human cancers has proven to be more challeng-
ing than for opportunistic viral infections. This reflects many issues, Target Antigens for Melanoma-Specific T Cells
including the difficulty isolating highly avid tumor-specific T cells Melanoma has served as a model for the discovery of human tumor anti-
from cancer patients, and evasion mechanisms that tumors employ to gens because T cells specific for melanoma cells can often be detected
avoid immune elimination including the local recruitment of regula- in the blood or the tumor microenvironment. A landmark in cancer
tory T cells (T REG ) or myeloid-derived suppressor cells, loss of antigen or immunotherapy was the identification by cDNA expression cloning of
HLA expression, and expression or secretion of inhibitory molecules or MAGE-1, which is a member of the cancer-testes antigen class of tumor
cytokines. 80–83 Additionally, a problem distinct from the results of T-cell associated antigens. Several additional shared tumor/self-melanocyte
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therapy for viruses is that transferred tumor-reactive T cells persisted differentiation antigens recognized by CD8+ and/or CD4+ T cells have
only transiently in most early clinical trials, even if high-dose interleu- been discovered, including differentiation proteins that function in nor-
kin (IL)-2 was given to support their survival. 84–88 mal melanocyte physiology such as tyrosinase, gp100, and MART-1;
The development of immune cell therapy for malignancy has and other cancer testis antigens such as NY-ESO-1. 78,99,100 Melanosome
focused on melanoma because target antigens have been identified antigens are also expressed in normal tissues (skin, retina), and toxicity
and this tumor has responded to nonspecific immune therapy with because of autoimmunity is a concern. Mutated proteins that arise as
IL-2, and on amplifying the graft-versus-leukemia (GVL) effect after a consequence of the genetic instability of tumors are being identified
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allogeneic HSCT because of the evidence that donor T cells mediate as critical targets of immune recognition, and these offer the greatest
tumor eradication in this setting. 90–92 The ability to engineer T cells promise for selectively targeting tumor cells without recognition of nor-
to have tumor specificity by introducing TCR genes that recognize mal cells. 101

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