Page 1170 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1134 PART NINE Transplantation

KEY CONCEPTS with aggressive lymphomas, ALL, MM, and CLL, resulting in long-
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Major Issues Related to Success of Allogeneic lasting remissions following heavy pretreatment. Developed in
the late 1980s and requiring decades of fine-tuning and extensive
Hematopoietic Stem Cell Transplantation clinical trials, CAR T cells have the ability to recognize and target
• Graft-versus-host disease (GvHD) tumor cells via their reprogrammed T-cell receptor (TCR) toward
• Graft-versus-tumor (GvT) responses the malignant cell and costimulatory molecules engineered into
• Kinetics and completeness of immune reconstitution the patient’s own T cells. This form of treatment engaging a
• Opportunistic infections from delayed immune reconstitution combination of gene therapy, cell therapy, and immunotherapy has
• Patient comorbid conditions increasing risk of toxicities led to unprecedented results in patients without robust treatment
• Chemotherapy sensitivity of disease being treated options for their aggressive malignancies or following relapse
after allo-HSCT. The primary limitation of CAR T–cell therapy is
Immunomodulation is frequently the first treatment option the need to identify tumor-specific antigens to avoid the serious
for patients in relapse after allo-HSCT, with rapid withdrawal toxicity of “on target” but “off tumor” response.
of immunosuppressive medications and infusion of donor T Another potential approach to augment GvT responses fol-
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cells. This treatment approach requires that donor T-cell chi- lowing HSCT to prevent or treat relapse is the use of checkpoint
merism be sustained to avoid rejection of effector cells through inhibitors, currently accomplished by mAb blockade of negative
an HvG mechanism. Patients with low-grade lymphoid malignan- regulatory signals from either cytotoxic T lymphocyte antigen-4
cies, such as CLL, indolent non-Hodgkin lymphoma (NHL), (CTLA4) or programmed death (PD)-1 proteins on the surface
mantle cell NHL, and CML have the highest likelihood of response. of activated T cells upon interaction with their respective ligands,
A survey of 25 transplantation programs identified 140 patients B7-2 (CD86) and PD-L1 (B7-H1), on APCs and tumor cells
who had received DLI and reported a complete response rate (Chapter 77). Checkpoint inhibitors show strong clinical efficacy
of 60% in patients with CML. Response rates were higher in in the treatment of relapsed hematological malignancies, such
patients with cytogenetic and chronic-phase relapse (75.7%) as CLL and Hodgkin lymphoma. 26,27 In a phase I dose-escalation
than in patients with accelerated-phase (33.3%) or blastic-phase study using the anti-CTLA4 mAb ipilimumab for relapse after
(16.7%) relapse, and almost 90% of these patients remained in allo-HSCT, Bashey et al. concluded that ipilimumab did not
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remission at 2 years after treatment. The activity of DLI in induce or exacerbate clinical GvHD but could cause organ-specific
AML and ALL is not as robust in comparison to that of in CML. immune adverse events and regression of malignancy following
However, it remains the main treatment strategy to treat relapse allo-HSCT. 28
following allo-HSCT. DLI can be used in combination with
chemotherapy to maintain control of disease control during the Adjuvant Therapy With HSCT
time required for the development of the GvT effect. The relatively higher incidence of relapse after high-dose therapy
The number of lymphocytes infused is important in achieving leads to the hypothesis that chemoablation therapy with auto-
the DLI effect, although it may be possible to induce GvT using HSCT, curative for some patients, could be viewed as a platform
doses of lymphocytes that are less likely to result in GvHD. A for other approaches effective in eliminating the minimal residual
large retrospective analysis demonstrated that using an initially disease (MRD) in patients destined to experience relapse.
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lower cell dose reduced GvHD and improved survival. One Additional or yet higher-dose chemotherapy or radiotherapy,
method to reduce GvHD is to genetically insert suicide genes unless directly targeted to the tumor, increases the risk of
into the T cells being given for DLI, allowing specific ablation nonhematopoietic toxicity and TRM from causes other than
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of these cells if this complication occurs. Another method to relapse. The correlation of more rapid lymphocyte recovery with
lower GvHD rates complicating DLI is to deplete the DLI product a decreased risk of relapse, although likely a reflection of host
of GvHD-inducing cells. Studies in mice have shown that naïve factors and not direct evidence of a GvT effect after auto-HSCT,
subset of CD8 T cells lead to more GvHD, whereas the effector supports attempts to use HSCT as a tumor-debulking platform
memory subsets (T EM ) of CD8 and CD4 T cells moderate the for posttransplantation immunotherapies. Immunotherapies are
graft-versus-leukemia (GvL) effect without causing GvHD. 22,23 of interest in this regard and include administration of post-
The delay in response between DLI and the development of a transplantation cytokines; the addition of tumor-specific antibod-
GvT effect suggests that only a minority of the cells infused ies, used before and/or after HSCT as an “in vivo purge”; and
recognize the tumor cell antigens and must undergo in vivo the development of tumor-specific vaccines, such as with tumor
expansion before the therapeutic effect is achieved. It may be antigen–pulsed dendritic cells (DCs). The immunoglobulin (Ig)
possible to develop leukemia-specific cytotoxic T cells in the idiotype found in most patients with MM and indolent NHL,
laboratory, decreasing the delay in effect and possibly increasing which is unique to the malignant clone, may serve as a unique
the GvT potential. Donor immunity can be transferred, at least tumor-associated antigen for DC pulsing. The treatment appeared
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transiently, to the host, as demonstrated by delayed-type transfu- to be well tolerated, and after vaccination, idiotype-specific
sion reactions to host red blood cells (RBCs), mediated by donor responses have been observed, characterized by T cell–proliferative
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lymphocytes transfused along with the HSC product. Adoptive responses with cytokine release and the production of antiidiotype
transfer of donor immunity against specific targets can be antibodies, although, again, a clinical benefit remains elusive.
achieved, but its persistence requires immunization of both the
donor and the recipient. A clinical utility for such manipulation CLINICAL HSCT
of the immune system has not yet been demonstrated, but it is
clearly of interest as a technique to prevent posttransplantation Sources of HSCs
infections and/or disease relapse. Bone marrow, peripheral blood stem cells (PBSCs), or UCB
A rapid and major leap in the field of adoptive transfer of are all appropriate sources of HSCs for transplantation, with
immunity is the development of CAR T–cell therapies for patients the primary differences being the quantities of HSCs in each