Page 1767 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 100 T-Cell Therapy of Hematologic Diseases 1571

melanoma who were given T cells expressing an NY-ESO-1 specific induced before infusion of the CAR-T cells. It is not yet known how
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αβTCR. Although most of these patients had no severe adverse the composition of the CAR affects the outcome, but patients can
events, toxicity was observed in normal tissues containing melano- achieve remission regardless the type of CAR costimulation (CD28
cytes such as skin and uvea in melanoma patients infused with or 4-1BB) used, although only 4-1BB costimulation appears to be
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MART-1 T cells. Colitis was also reported in patients with meta- associated with prolonged CAR–T-cell engraftment. Because the
static colon carcinoma who received T cells expressing a TCR directed CD19 target molecule is also expressed by normal B cells, the eradica-
to the carcinoembryonic antigen that is also expressed at low level in tion of B-cell leukemia is also associated with B-cell aplasia, which
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normal epithelia cells of the gut. Thus T cells with high-affinity was sustained during the period of robust CAR–T-cell engraftment.
transgenic TCR may produce “on target” but “off organ” toxicities to CD19-specific CAR-T cells have been successfully used in both
normal tissues that physiologically express the target antigen at low autologous and allogeneic (after HSCT) settings.
level. The first TCR gene therapy trial for patients with acute leuke- Despite their remarkable success, administration of CD19–CAR-T
mia targeting WT1 is currently recruiting patients. cells is also associated with potentially lethal acute toxicity caused by
The major problem of TCR gene transfer in polyclonal T lym- a profound perturbation of the immune system, often termed the
phocytes harboring their own native αβTCR was hypothesized to be systemic inflammatory response syndrome, which is manifest by
the “cross-pairing” between transgenic α or β receptor chains and the hyperpyrexia, hypotension, and respiratory distress with high levels
reciprocal endogenous TCR α- and β-chains, that could create loss of circulating proinflammatory cytokines. Although investigators can
of function or—and potentially worse—gain of function receptors usually control this unwanted outcome, larger scale clinical studies
that may produce autoimmune disease, an adverse effect clearly will be essential to assess the feasibility of safely introducing the
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demonstrable in mouse models. These events have not been reported approach into more generalized clinical practice.
in clinical trials so far, but unfortunately other unexpected toxicities CAR–T-cell therapies for other hematologic malignancies such as
have been observed. Patients with myeloma or melanoma were given myeloid leukemia and multiple myeloma are also in preclinical stages
T cells modified to express a TCR specific for MAGE-A3 that had or in phase I clinical trials. While targeting several candidate antigens
been synthetically affinity-enhanced. Two of the recipients rapidly such as B-cell maturation antigen (BCMA) or CS1 could be effective
developed lethal cardiotoxicity caused by an unanticipated cross- in controlling the proliferation of the malignant plasma cells of
reactivity of the transgenic TCR against peptide epitopes derived multiple myeloma without causing “on target” toxicities, the selection
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from Titin, which were expressed only by cardiac myocytes. In a of antigens that can selectively control myeloblasts without causing
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second study, the infusion of T cells expressing a transgenic high myelosuppression remains more challenging. Recent clinical experi-
affinity MAGE-A3 TCR caused lethal neurotoxicity possibly caused ence using CD33-specific CAR–T-cells in a single patient with acute
by the simultaneous cross-reactivity of a MAGE-A12-derived peptide myeloid leukemia suggests that the only potential clinical application
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expressed in human brain. These results strongly indicate that T of CARs targeting shared myeloid antigen is the induction of remis-
cells engineered with high-affinity TCR can be effective, but can also sion in preparation for hematopoietic stem cell transplantation. 26
reveal unexpected and lethal cross-reactivity with other peptide epit-
opes that would not be recognized by TCR with more physiologic
binding affinity. 18,21 While such unanticipated toxicities may be Optimizing T-Cell Trafficking and Overcoming Tumor
avoided by ever more extensive preclinical evaluation, reliance on Immune Evasion
“superaffinity” TCR may be intrinsically hazardous.
The expression of transgenic TCRs or CARs in T lymphocytes
confers potent cytotoxic activity and potential long-term persistence
Chimeric Antigen Receptors to these cells. However, other functional T-cell properties may need
to be addressed to maximize their antitumor effects. Table 100.2 and
The cytotoxic activity of T cells through their native or transgenic Fig. 100.1 summarize some of the T-cell modifications that may
TCR is MHC-restricted so that multiple distinct transgenic αβTCR optimize the antitumor activity of T lymphocytes. For example,
would be required to recognize tumor antigens associated with the CD19-specific CAR-T cells may be more effective for the treatment
multiple MHC polymorphisms in a human population, precluding of ALL than of lymphoma in part because they more efficiently
a “universal” receptor. In addition, tumor cells can downregulate eliminate tumor cells from the circulation and bone marrow than the
MHC molecules and avoid immune recognition by conventional lymph nodes. Many lymphomas are characterized by a particular
TCRs. In an attempt to overcome this limitation, MHC unrestricted chemokine milieu to which engineered T cells can be adapted. For
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CARs have been generated. CARs are most commonly prepared by example, Hodgkin lymphomas may produce high levels of TARC,
joining the light and heavy chain variable regions of a monoclonal and T cells coexpressing a CAR specific for the Hodgkin disease–
antibody expressed as a single-chain Fv (scFv) molecule to the cyto- associated CD30 antigen and a transgenic chemokine receptor CCR4
plasmic signaling domains derived from CD3ζ cytoplasmic and have significantly enhanced traffic to the tumor and consequently
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intracytoplasmic endodomains derived from costimulatory molecules better antitumor activity in animal models. Even when tumor-
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such as CD28, 4-1BB and OX40. Thus when CARs are expressed specific T cells efficiently reach the tumor-environment, other tumor-
by polyclonal T lymphocytes or VSTs, they can combine the antigen associated factors may hamper T-cell survival and function. For
specificity of an antibody with the cytotoxic properties of T cells, example, many tumors, including hematologic malignancies, and
together with the costimulatory signals provided by professional their tumor-associated stroma produce transforming growth factor
antigen presenting cells that allow survival and proliferation of acti- (TGF)-β, which favors the development of immune tolerance and
vated T lymphocytes. Since CARs bind to target antigens in an T-cell anergy, inducing T effector cell growth arrest with induction
HLA-unrestricted manner, they are resistant to many of the tumor of regulatory T cells. Transfection of a dominant negative form of
immune evasion mechanisms, such as downregulation of HLA class TGF-β RII (dnTGF-β RII) confers resistance to the antiproliferative
I molecules or failure to process or present proteins, used by tumor effects of TGF-β and improves the persistence of T cells and antitu-
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cells to escape immune attack. Adoptive transfer of polyclonal acti- mor effects in preclinical models, and such approach is currently
vated T cells expressing a second generation CD19-specific CAR being studied in patients with EBV-associated lymphomas.
caused impressive clinical responses in patients with ALL and lym- Achievement of sustained clinical responses upon T-cell transfer
phomas with >75% complete response rates in relapsed/refractory is strongly dependent on in vivo T-cell expansion and persistence,
ALL patients in several phase I clinical trials (Table 100.1). The small which in turn requires the infused T cells to contain a population
size and significant heterogeneity of these studies precludes definitive with a stemness/memory signature and the availability of cytokines
conclusions, but the data suggest that adoptive transfer of CAR-T that sustain T-cell replication and survival. We do not yet know the
cells is more effective in patients with B-ALL than in other B-cell optimal means by which stem/memory T cells can be preserved
malignancies. The effects also seem greatest when lymphopenia is before adoptive transfer. 27,28 Nonetheless it is clear that infusion of