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

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Techniques for Isolation and Adoptive Transfer of and durable tumor regression in this patient. These results illustrate
Melanoma-Specific T Cells the potential of patient specific T-cell therapy targeting immunogenic
The adoptive transfer of tumor-specific T-cell clones or oligoclonal pop- mutations present in their tumor and highlight the need to apply
ulations of T cells expanded ex vivo can, in principle, allow control over advanced genomic technologies to the discovery of targets for immune
the magnitude and function of the tumor-reactive T-cell response in therapy in cancer. 108,120
the patient. If the tumor is easily accessible, tumor-reactive T cells can Collectively, significant progress has been made in cellular ther-
sometimes be isolated directly from the tumor biopsies by culture in apy for melanoma, but additional studies are necessary to define the
high-dose IL-2. Melanoma-reactive T cells can also be isolated using optimal and safest regimens for adoptive therapy with tumor-reactive
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autologous dendritic cells pulsed with synthetic peptide antigen, but T cells. Advances in our understanding of the role of individual cytok-
this approach can enrich low-avidity T cells that have a limited capacity ines in T-cell survival in vitro and in vivo, or the regulation of T-cell
to persist and function in vivo. 103 activation and homeostasis will provide new opportunities for improv-
Initial clinical trials of T-cell therapy for melanoma employed ing the persistence of in vitro expanded T cells after transfer, perhaps
CD8+ T-cell clones specific for MART-1 or gp100; or clonal or polyclonal obviating use of toxic chemoradiotherapy to deplete lymphocytes
melanoma-reactive T cells derived and expanded from TILs. 84,104,105 The before T-cell infusions. Most of the initial efforts have focused on the
transferred T-cell clones given with low-dose IL-2 mediated transient CD8+ T-cell response to tumor antigens, but newer data highlights the
antitumor activity in some patients with advanced disease, but did not potential of tumor-specific CD4+ T cells. Combining T-cell therapy
persist for long term. The response rate was higher in patients treated with targeted depletion of T REG , checkpoint inhibitors, and vaccines is
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with polyclonal TILs and high-dose IL-2. T-cell persistence was highly also under investigation, and may help overcome mechanisms by which
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variable and only rarely sustained despite the infusion of large T-cell tumors evade elimination by limiting the quantity and quality of the
numbers (up to 10 ). The inability of T cells to persist in vivo could host response.
11 84,104
reflect an inadequate antigen-specific CD4+ Th response, terminal dif-
ferentiation of T cells during expansion, activation-induced T-cell death
at the tumor site, or cell death as a consequence of IL-2 withdrawal. 84,106 CELLULAR THERAPY OF LEUKEMIA
A major advance in the field was the demonstration that the Allogeneic donor T cells contained in or derived from the stem cell
transferred human T-cell persistence and therapeutic efficacy could graft can mount a GVL effect that can contribute to the eradication
be improved by pretreatment of the patient with a lymphodepleting of hematologic cancers, including leukemia. This is underscored by
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regimen containing cyclophosphamide and fludarabine. 107,108 In these studies on the antitumor effects of infusions of unselected donor lym-
studies, high-dose IL-2 was administered daily after TIL transfer until phocytes (DLI) given to patients who relapse after allogeneic HSCT.
toxicity required it be discontinued. A subset of the patients achieved DLI can have potent antitumor effects in patients with relapsed chronic
prolonged high-level engraftment of one or a few tumor-reactive CD8+ myeloid leukemia, but has been less effective in acute leukemias, and
T-cell clonotypes present in the infused polyclonal T-cell product. 107–110 often complicated by the development of acute and chronic GVHD.
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In a followup analysis of a large cohort of patients, the overall and com- The identification of leukemia-associated antigens that can be targeted
plete response rates were approximately 50 percent and 20 percent, to selectively promote a GVL effect without causing GVHD remains an
respectively. 108,111 The antitumor activity correlated with the persis- important goal. 92,121
tence of high levels of transferred tumor-reactive CD8+ T cells. Several
mechanisms make the lymphopenic environment favorable for T-cell Target Antigens for Leukemia-Specific T Cells
transfer, including less competition for homeostatic cytokines such as GVHD and GVL effects usually coexist, but a GVL effect can be observed
IL-15 and IL-7 that promote lymphocyte survival, 112,113 and the elim- after HSCT in the absence of GVHD. Thus, it is presumed there are
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ination of CD4+CD25+ T REG cells. Studies in murine models have antigens that are expressed by leukemia cells that can be targeted by
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confirmed that severe lymphodepletion can be exploited to improve the allogeneic T cells. Several categories of such antigens have been identi-
antitumor efficacy of the transferred T cells. The addition of 2 Gy or fied. These include (1) minor histocompatibility antigens (mHAgs) that
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12 Gy of total-body irradiation to the lymphodepleting treatment with are selectively expressed in hematopoietic cells including leukemic cells,
cyclophosphamide and fludarabine before TIL transfer increased the (2) tumor-specific proteins resulting from chromosome translocations
response rate to 52 percent and 72 percent, respectively. The results or mutations, and (3) normal proteins that are overexpressed in leu-
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of TIL therapy in a metastatic tumor that is unresponsive to conven- kemic cells. Proteins in the latter two classes could be targets both in
tional therapy were achieved with moderate toxicity, demonstrating the the transplantation and nontransplantation setting, whereas mHAgs are
encouraging potential of this therapy. only relevant after allogeneic HSCT.
Studies of the mechanisms of tumor eradication in melanoma
are providing insights for treatment of other cancers with T-cell ther- Minor Histocompatibility Antigens
apy. Exome sequencing of melanoma has shown that the frequency of The increased potency of the GVL effect after allogeneic HSCT compared
mutational events is high, 101,117 and detailed analysis of the specificity with syngeneic HSCT emphasizes the importance of disparity in major
of TILs showed that in addition to T cells specific for shared tumor/ HLA and mHAgs for immune-mediated eradication of malignancy. 90,122
self-melanocyte differentiation antigens, such mutated gene prod- Class I and class II molecules on recipient T cells display mHAgs, which
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ucts encoded neoepitopes that were often targets of immune recogni- are peptides derived from proteins that differ between the donor and
tion. 101,108,119 The identification of neoepitope T cells in nonmelanoma recipient as a result of genetic polymorphism. 92,123 In murine models,
cancers is of considerable interest because mutations in other tumors the adoptive transfer of T cells specific for a single mHAg eradicated
may be similarly targeted. In one example, TIL therapy was used to leukemia without causing GVHD. In humans, donor T cells reac-
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successfully treat a patient with metastatic cholangiocarcinoma. tive with recipient mHAgs can be isolated after transplantation from
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Whole-exome sequencing of the tumor identified a mutation within the most allogeneic HSCT recipients. Analysis of the specificity of such
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erbb2 interacting protein (ERBB2IP) that was recognized by a subset of T-cell clones shows that many mHAgs are expressed preferentially in
CD4+ T cells in the TIL product. Treatment with a greater than 95 per- hematopoietic cells, including leukemic blasts, and might permit the
cent pure population of mutation-reactive T cells resulted in dramatic separation of GVL from GVHD. mHAg-specific CD8+ CTLs prevent
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