IntroductionLow-grade non-Hodgkin lymphomas (B-NHLs) and B-cell chronic lymphocytic leukemia (B-CLL) are generally characterized by a smoldering clinical course. 1,2 Nonetheless, these diseases slowly progress and require intervention. Although remission can be obtained with chemotherapy and antibody directed to B-cell antigens such as CD20, most patients ultimately have relapses. [3][4][5] More aggressive treatments including allogeneic stem cell transplantation may eradicate disease, apparently in part by a T cell-mediated graft-versus-leukemia (GVL) effect. [6][7][8] Unfortunately, their high rate of morbidity and mortality limits their application to younger patients. 9,10 Because these malignancies are sensitive to both T cell-mediated and antibody-mediated cytotoxic effector functions, there has been increasing interest in combining these approaches and recruiting the host immune system to help eradicate the disease that remains after conventional treatments. Anti-idiotype vaccine or whole tumor cell-based vaccines have been used in several clinical trials, but although antitumor activity was observed, the effects were often limited and transient. [11][12][13][14] An alternative means of recruiting both the cellular and humoral arms of the immune response is to adoptively transfer T cells genetically modified to express a B cellspecific antibody incorporated in an artificial chimeric T-cell receptor (CAR). 15,16 These molecules combine the antigen-binding property of monoclonal antibodies with the lytic capacity and potential longevity of T lymphocytes to provide an enhanced antitumor effect. 16 Because B-NHL and B-CLL stably express CD19 or CD20 antigens, adoptive transfer of CD19-or CD20-specific CARs to T lymphocytes has been proposed. [17][18][19][20] However, adoptively transferred T cells, unlike monoclonal antibodies, may have almost indefinite persistence 21 so that success of this approach would likely be associated with long-term impairment of humoral immunity. We now propose an alternative target for chimeric T cells. B lymphocytes express surface monoclonal immunoglobulins with either or light chains. Because expression of / is clonally restricted, and because low-grade B-NHL and B-CLL are themselves clonal, the malignant cells in a given individual will express either or light chain. 22 Chimeric T lymphocytes targeting the light chain expressed by the tumor should spare normal B cells expressing the reciprocal light chain. Because no functional differences have been found between antibodies containing the or chains 23 and because light chain deficiency has been described in animals 24 and humans 24,25 without increased susceptibility to infection, sparing the normal population of B lymphocytes expressing the nontargeted light chain should have minimal adverse effects on patient immunity. We now demonstrate the feasibility of this approach using a light chain-specific chimeric T-cell receptor. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From culture with RPMI 1640 medi...
As significant numbers of acute myeloid leukemia (AML) patients are still refractory to conventional therapies or experience relapse, immunotherapy using T cells expressing chimeric antigen receptors (CARs) might represent a valid treatment option. AML cells frequently overexpress the myeloid antigens CD33 and CD123, for which specific CARs can be generated. However, CD33 is also expressed on normal hematopoietic stem/progenitor cells (HSPCs), and its targeting could potentially impair normal hematopoiesis. In contrast, CD123 is widely expressed by AML, while low expression is detected on HSPCs, making it a much more attractive target. In this study we describe the in vivo efficacy and safety of using cytokine-induced killer (CIK) cells genetically modified to express anti-CD33 or anti-CD123 CAR to target AML. We show that both these modified T cells are very efficient in reducing leukemia burden in vivo, but only the anti-CD123 CAR has limited killing on normal HSPCs, thus making it a very attractive immunotherapeutic tool for AML treatment.
This phase I multicenter study was aimed at assessing the feasibility and safety of intravenous administration of third party bone marrow-derived mesenchymal stromal cells (MSC) expanded in platelet lysate in 40 patients (15 children and 25 adults), experiencing steroid-resistant grade II to IV graft-versus-host disease (GVHD). Patients received a median of 3 MSC infusions after having failed conventional immunosuppressive therapy. A median cell dose of 1.5 × 10(6)/kg per infusion was administered. No acute toxicity was reported. Overall, 86 adverse events and serious adverse events were reported in the study, most of which (72.1%) were of infectious nature. Overall response rate, measured at 28 days after the last MSC injection, was 67.5%, with 27.5% complete response. The latter was significantly more frequent in patients exhibiting grade II GVHD as compared with higher grades (61.5% versus 11.1%, P = .002) and was borderline significant in children as compared with adults (46.7 versus 16.0%, P = .065). Overall survival at 1 and 2 years from the first MSC administration was 50.0% and 38.6%, with a median survival time of 1.1 years. In conclusion, MSC can be safely administered on top of conventional immunosuppression for steroid resistant GVHD treatment. Eudract Number 2008-007869-23, NCT01764100.
Chimeric antigen receptor (CAR)-redirected T lymphocytes are a promising immunotherapeutic approach and object of pre-clinical evaluation for the treatment of acute myeloid leukemia (AML). We developed a CAR against CD123, overexpressed on AML blasts and leukemic stem cells. However, potential recognition of low CD123-positive healthy tissues, through the on-target, off-tumor effect, limits safe clinical employment of CAR-redirected T cells. Therefore, we evaluated the effect of context-dependent variables capable of modulating CAR T cell functional profiles, such as CAR binding affinity, CAR expression, and target antigen density. Computational structural biology tools allowed for the design of rational mutations in the anti-CD123 CAR antigen binding domain that altered CAR expression and CAR binding affinity without affecting the overall CAR design. We defined both lytic and activation antigen thresholds, with early cytotoxic activity unaffected by either CAR expression or CAR affinity tuning but later effector functions impaired by low CAR expression. Moreover, the anti-CD123 CAR safety profile was confirmed by lowering CAR binding affinity, corroborating CD123 is a good therapeutic target antigen. Overall, full dissection of these variables offers suitable anti-CD123 CAR design optimization for the treatment of AML.
Summary
Current therapeutic regimens for acute myeloid leukaemia (AML) are still associated with high rates of relapse. Immunotherapy with T‐cells genetically modified to express chimeric antigen receptors (CARs) represents an innovative approach. Here we investigated the targeting of the interleukin three receptor alpha (IL3RA; CD123) molecule, which is overexpressed on AML bulk population, CD34+ leukaemia progenitors, and leukaemia stem cells (LSC) compared to normal haematopoietic stem/progenitor cells (HSPCs), and whose overexpression is associated with poor prognosis. Cytokine‐induced killer (CIK) cells were transduced with SFG‐retroviral‐vector encoding an anti‐CD123 CAR. Transduced cells were able to strongly kill CD123+ cell lines, as well as primary AML blasts. Interestingly, secondary colony experiments demonstrated that anti‐CD123.CAR preserved in vitro HSPCs, in contrast to a previously generated anti‐CD33.CAR, while keeping an identical cytotoxicity profile towards AML. Furthermore, limited killing of normal monocytes and CD123‐low‐expressing endothelial cells was noted, thus indicating a low toxicity profile of the anti‐CD123.CAR. Taken together, our results indicate that CD123‐specific CARs strongly enhance anti‐AML CIK functions, while sparing HSPCs and normal low‐expressing antigen cells, paving the way to develop novel immunotherapy approaches for AML treatment.
These findings support the hypothesis that TH-17 are involved in the active phases of GVHD and may represent a novel cellular target for developing new strategies for GVHD treatment.
Mesenchymal stem cells (MSCs) were first isolated more than 50 years ago from the bone marrow. Currently MSCs may also be isolated from several alternative sources and they have been used in more than a hundred clinical trials worldwide to treat a wide variety of diseases. The MSCs mechanism of action is undefined and currently under investigation. For in vivo purposes MSCs must be produced in compliance with good manufacturing practices and this has stimulated research on MSCs characterization and safety. The objective of this review is to describe recent developments regarding MSCs properties, physiological effects, delivery, clinical applications and possible side effects.
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