Allogeneic transplantation as anticancer immunotherapy

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ScienceDirect Allogeneic transplantation as anticancer immunotherapy Simrit Parmar1 and David S Ritchie2 Allogeneic stem cell transplantation (AlloSCT) utilizes HLAmatched donor bone marrow or peripheral blood stem cell grafts to reconstitute haematopoiesis and immunity in patients with bone marrow failure or hematological malignancies. It is now clear that much of the anti-cancer effect of AlloSCT is due to the ability of engrafting donor derived lymphocyte populations to eradicate residual malignant clones, through a phenomenon known as the graft-versus-tumor (GVT) effect. Recognition of the importance of GVT in the long-term control of cancer has allowed substantial reductions in the pretransplant conditioning intensity, leading to the development of reduced-intensity or even non-myeloablative transplant regimens in some patient groups. These reduced intensity regimens still allow donor cell engraftment and GVT, whilst reducing the morbidity and mortality associated with traditional myeloablative conditioning. Through clinical observations and experimental models of AlloSCT substantial insights have been provided into the mechanisms of immunological control of malignancy even outside the setting of AlloSCT, providing an opportunity to duplicate these anti-cancer mechanisms via non-allogeneic immunotherapies. Addresses 1 MD Anderson Cancer Centre, Houston, TX, USA 2 Royal Melbourne Hospital, Melbourne, Australia Corresponding author: Ritchie, David S. ([email protected])

Current Opinion in Immunology 2014, 27:38–45 This review comes from a themed issue on Tumour immunology Edited by Philip K Darcy and David S Ritchie For a complete overview see the Issue and the Editorial Available online 15th February 2014 0952-7915/$ – see front matter, # 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coi.2014.01.010

Introduction The application of allogeneic stem cell transplantation (AlloSCT) for treatment of haematologic malignancy can be considered the most widely applied and, to date, the most successful method of delivering immunotherapy against cancer. The infusion of donor hematopoietic stem cells along with allogeneic lymphoid populations after immunosuppressive and tumor controlling conditioning chemotherapy or chemo-radiation therapy results in reconstitution of hematopoiesis, expansion of lymphoid effectors, recognition of minor histocompatibility antigens on tumor targets and eradication of residual malignancy. This process is referred to as the graft-versustumor (GVT) effect. Current Opinion in Immunology 2014, 27:38–45

However, important limitations to the delivery of AlloSCT transplantation as cellular therapy exist. To date it has been difficult to separate the beneficial impact of the GVT effect from the detrimental and often life-threatening toxicity of graft versus host disease (GVHD). Another challenge is to target the intensity of pre-transplant conditioning to simultaneously allow tumor control, whilst avoiding excess toxicity. Nonetheless, AlloSCT has provided important clinical and biological insights into the potency and limitations of cellular therapy against cancer.

The potency of GVT effect The potency of GVT effect in haematologic malignancies is clearly demonstrated in the outcome of patients suffering from leukemia or lymphoma subtypes, which are generally incurable by standard chemotherapy alone but are able to undergo sustained, durable remission following allogeneic transplantation. This is most clearly demonstrated in patients with acute myeloid leukemia (AML) in first remission, in whom stratification by cytogenetics or molecular risk indicates an anticipated longterm survival of less than 10% following conventional chemotherapy but can enjoy long term survival likelihoods of between 30% and 50% following AlloSCT [1]. Similar relationships have been identified in the setting AlloSCT for lymphoma and multiple myeloma, although in some instances the increased rates of transplant related mortality from organ toxicity, infection and/or GVHD may limit the advantageous impact of AlloSCT on reducing relapse rate. Recent registry data has identified a clear link between the onset of GVHD and a lower likelihood of disease relapse following allogeneic transplantation for chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and AML with lesser impacts being demonstrated in B-cell non-Hodgkin’s lymphoma (NHL) [2]. The realization of the importance of the GVT effect was largely serendipitous through the combined observations of 1. Improved control of haematologic malignancy in the setting of GVHD [3], 2. Loss of the tumor control efficacy when grafts were depleted of T-cells (undertaken to reduce the risk of GVHD) [4], 3. The ability of some patients to attain further remissions merely on the removal of post-AlloSCT immunosuppression [5] and 4. The observation that tumors maybe eradicated when additional immune effectors were infused after transplantation in the form of donor lymphocyte www.sciencedirect.com

Allogeneic cancer immunotherapy Parmar and Ritchie 39

Figure 1

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Allogeneic stem cell transplant: The high dose chemotherapy included as part of the conditioning regimen helps in controlling any residual recipient leukemia, however, donor mixed chimerism may allow the persistence of minimal residual disease which can be further eliminated by planned DLI. DSC: donor stem cell; DT: donor T-cell; D: donor cells; R: recipient cells; RL: recipient leukemia; DNK: donor NK cell; DB: donor B cell; DLI: donor lymphocyte infusion.

infusions (DLI) [6]. Many of these original observations were made in the setting of AlloSCT for patients with CML [3]. However, these same observations have also been made in other hematological malignancies including AML [7], ALL [8], NHL and chronic lymphocytic leukemia (CLL) [9], Hodgkin lymphoma [10] and myeloma [11]. Examples of efficacy of the GVT effect in solid malignancy are less available however there is a clear immunemediated allogeneic GVT effect in renal cell carcinoma [12] and breast cancer [13,14]. An overview of different aspects of GVT effect associated with AlloSCT is summarized in Figure 1. As the importance of post-AlloSCT immune reconstitution as a requisite for GVT has been confirmed, there is now an increasing recognition that the efficacy of AlloSCT itself could possibly be disconnected from the intensity of pre-transplant conditioning regimen. The understanding of this concept gave rise to the increased application of reduced intensity conditioned (RIC) allogeneic transplants where anti-tumor efficacy is mediated largely or solely via the GVT effect. RIC transplantation now accounts for one third of AlloSCT performed internationally [15] and has seen the more wide spread application of AlloSCT to patients who would have been previously excluded due to poor tolerance of intensive conditioning regimens as a consequence of either age or comorbidity. To date, RIC www.sciencedirect.com

transplantation has been used across all subtypes of blood cancers with the clearest therapeutic impact seen in acute leukemia, chronic lymphocytic leukemia and low-grade lymphoma.

Mechanisms of action for GVT in allogenic transplantation The GVT effect has largely been attributable to cytotoxic T lymphocytes (CTL) derived from mature donorderived CD8+ T lymphocytes in both experimental models and in clinical observation [16]. However, it is highly likely that other effector lymphocyte populations play a role in the eradication of tumors following AlloSCT. The best evidence for the efficacy of other lymphocyte populations has been derived in the setting of haploidentical transplantation in which complete T-cell depletion is undertaken before the infusion of the donor graft. Despite removal of all potential T-cell clones, potent control of AML (and less so ALL) has been identified [17]. Dissection of the NK mediated control of acute leukemia in this setting identified that mismatching of NK inhibitory ligands promoted the eradication of both malignant haemopoietic clones and residual recipient antigen presenting cells (APCs) thereby providing a potent GVT effect whilst limiting the onset of GVHD (Figure 2). These initial observations have been difficult to duplicate and the role of NK receptor mismatching has often been Current Opinion in Immunology 2014, 27:38–45

40 Tumour immunology

Figure 2

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Mechanism of GVT/GVHD in AlloSCT. NK cell attacks the target cells including the tumor cell and stroma in the absence of the surface expression of MHC class I molecule. Such mismatch in the killer immunoglobulin-like receptor (KIR) ligands in the GVH direction leads to killing of the recipient antigen presenting cells (APCs) and thus leading to protection from GHVD. CD4 helper T cell sends maturation signal to the dendritic cell which in turn engages the CD8+ cytotoxic T cell to kill the target tumor cell. CD4+ T-cell also directly activates the CD8+ T-cell via the CD40-CD40 ligand pathway. In addition CD4+ helper T-cell engages B-cell via the CD40-CD40 ligand pathway as well as through the T-cell receptor engagement with the MHC-II peptide in order to generate antibody production that utilizes the antibody dependent cellular toxicity (ADCC) mediated cell death leading to the GVL effect. Activated CD8+ T-cell and the B-cell can also target the normal tissue leading to GVHD.

conflicting. Nonetheless, NK cell potency in the allogeneic setting has lead to increasing recognition of these cells being utilized for adoptive cellular therapy including the infusion of immuno-selected CD3 /CD56+ NK cells, early after allogeneic transplantation as a potential substitute to unselected DLI (NCT01853358). However there may be dissociation between the in vitro potency of NK cells and their in vivo efficacy perhaps due to diminished activation status following their adoptive transfer and accumulation in the tumor bed [18]. Optimization of donor NK cell potency may require selection of specific cell subsets with expression of appropriate KIR molecules [19] in order to limit the likelihood of NK cell inactivation, or alternatively by engineering the surface expression of tumor antigen receptors on NK cells [20]. Current Opinion in Immunology 2014, 27:38–45

Other populations of lymphocytes have also been identified in experimental settings to be potent effectors for the GVT effect including CD4+ T-cells, that are known to play a central role as helper cells in triggering and maintaining immune responses [21]. CD4+ T cells provide help by inducing maturation of dendritic cells, stimulation of CD8+ T cells as well as deliver essential signals for B-cells to produce IgG antibodies [22,23]. In NOD/SCID mouse model for human ALL and CML, highly purified CD4+ DLI eradicated the leukemic cells and the anti-tumor immunity was mediated by a polyclonal CD4+ T cell response comprising cytokine-producing T-helper and cytolytic T-effector cells directed against the mismatched HLA-class II molecules of the patients [24]. Furthermore, antigen-specific GVL effect www.sciencedirect.com

Allogeneic cancer immunotherapy Parmar and Ritchie 41

comprising of allo T-cell and auto B-cell response has also been mediated by the alloreactive CD4+ T cells against PTK2B, a target for antibodies in post-AlloSCT relapsed CML patients [25,26]. More recently, donor derived CD4+ T cell responses against HTLV-1 bZIP factor (HBZ) [27] and Tax-epitope [28] have been reported only in the post AlloSCT setting in adult T cell leukemia/ lymphoma (ATL). The ability of donor derived CD4+ T cells to recognize the antigen as foreign and generate antigen-specific immune response contributes to the GVT effect. Whilst it is likely that the major mechanism of action of these lymphocyte populations is direct cytotoxicity against tumor targets, there is also likely to be indirect micro-environmental effects resulting in loss of supportive tumor stroma. Indirect evidence of this exists in the setting of GVHD where much of the organ toxicity of experimental gut GVHD is mediated through cytotoxic targeting of non-haemopoietic APCs [29]. Similarly, other mechanisms of action may include bystander affects mediated by inflammatory cytokines and potentially antibody production [30].

Immune escape after AlloSCT There is evidence that AlloSCT may have limitations in its ability to control all of the malignant subclones. Acute leukemia that has escaped from immunological control and relapses after AlloSCT is more likely to present in an immuno-privileged anatomical site and more likely to show evidence of clonal evolution [31]. One of the potential mechanisms of escape of acute leukemia from immunological control by donor lymphocyte populations is down regulation of HLA class I and thus impaired recognition by CTL. Loss of antigen/MHC-I has been described in a wide range of human cancers [32], including relapsing AML [33,34]. Further mechanisms of loss of control of disease by allogeneic lymphoid effectors are the escape of tumor clones in immuno-privileged sites and, through the process of NK mediated immuno-editing, the emergence of subclones which have lost expression of the activating ligands to NK cell receptors (Chan et al., unpublished observations). In an attempt to overcome the current limitations of donor-derived lymphoid control of tumor, combination therapies aimed at enhancing tumor targeting have been proposed. Perhaps the most exciting developments to enhance the efficacy of donor derived lymphoid populations against tumors have either been to combine such therapy with checkpoint blockade inhibitors such as antiCTLA4 (Ipilimumab) [35] or anti-PD1 (Nivolumab) [36]. These therapies have shown substantial efficacy as single agents and are a logical choice for combination of allogeneic cellular therapies. There is evidence that post-AlloSCT CTL activity can be enhanced to induce anti-tumor affects through the use of Ipilimumab [37]. www.sciencedirect.com

On the basis of favorable outcomes of CTLA-4 blockade in human solid tumors, it is now being evaluated in clinical trials of patients with relapsed AML (NCT01757639) or following AlloSCT (NCT01822509 and NCT00060372). Blockade of PD1–PDL1 interactions similarly enhances the post-AlloSCT GVT effect in an animal model of AML [38] and more recently, there is increased evidence that relapse in AML clones have higher expression of PD1 resulting in active suppression of tumor infiltrating lymphocytes. These observations suggest that anti-PD1 therapy would be a logical adjunct to the prophylactic control of AML (and potentially other tumor targets) in the post-AlloSCT setting. To date anti-PD1 therapy is yet to be explored in this setting clinically. Whilst the ability of AlloSCT to control malignancy in some instances is largely dependent on the induction of the GVT effect, some tumors still require a potent conditioning regimen in combination with an allogeneic graft for optimal control. Therefore dose intensity of the conditioning regimen maybe important in patients with rapidly progressive diseases or those who are entering into transplant with significant residual tumor bulk. This likely reflects the outgrowth of tumor and/or the active suppression of the immune system by the tumor before effective immune reconstitution can occur in the posttransplant setting. In order to try and counter this escape of tumor before a full engraftment of the immune effectors, some strategies have called for the infusion of additional lymphoid populations either when there is ongoing evidence of detectable tumor pre-transplant or in an attempt to prevent the re-emergence of tumor after transplant. In some diseases, the administration of DLI in the setting of either molecular or minimal residual disease relapse has been associated with re-induction of remission. In other instances, the prophylactic administration of DLI before the identification of relapse appears to reduce the risk of relapse as the GVT effect is optimized. Unfortunately, in the setting of frank progressive disease, DLI alone is often inadequate to regain control over tumor growth, likely due to active suppression of effector lymphoid population. In a small minority of such patients, long-term control of tumor maybe regained by the combination of further debulking chemotherapy followed by the administration of donor-derived T cells [39,40]. As the ability of AlloSCT to cure patients with malignancy that is not amenable to control by chemotherapy alone is increasingly realized and in turn as the mechanism of this efficacy is identified as being driven by the GVT effect derived from the donor immune effectors which is most potent in the setting of minimal residual disease, there is now increasing pressure to identify novel strategies to enhance the GVT effect before frank relapse. Novel mechanisms to enhance the efficacy of Current Opinion in Immunology 2014, 27:38–45

42 Tumour immunology

the engrafting donor lymphoid population may be necessary as it is possible that donor T-cells undergo senescence following AlloSCT or in the post-transplant DLI setting [41]. To promote post-AlloSCT T-cell activation, some investigators have utilized a selected population of Tcells, which have either been pre-activated or antigen selected to improve their efficacy post infusion [42]. Similarly, DLI have been combined with infusion of tumor-antigen directed antibodies in an attempt to increase the likelihood of antibody directed cellular cytotoxicity [43]. Additional novel strategies aimed at promoting the GVT effect in AML have included the administration of hypomethylating agents including Azacytidine either alone [44] or in combination with DLI [45]. This strategy appears to be safe and is associated with the increased expression of leukemia specific antigens and enhancing the targeting of CTL populations to AML clones. Intriguingly, azacytidine may increase induction of regulatory T-cell populations in vivo therefore limiting the onset of GVHD [46]. More recently, however, there is evidence that azacytidine may also impair NK cell activity in patients undergoing AlloSCT, suggesting that care may need to be applied when utilizing emerging combinations of novel therapies. Other strategies to enhance the efficacy of donor derived lymphocyte populations post-transplant include vaccination approaches which are being used in the setting of AML utilizing the PR-1 epitope of PR-3 [47] or WT1, also in the setting of AML [48]. Recently, the ability to genetically modify T-cells or NK cells to express chimeric antigen receptors (CAR) has resulted in potent affected population of lymphocytes directed against specific tumor targets. The most effective of these appears to be T-cells modified to express chimeric CD19 receptors, which have shown efficacy against CLL and B-cell ALL [49]. Whilst most of the therapies have utilized autologous T-cells, donor derived T-cells have also been utilized after AlloSCT [50]. CAR positive NK cells have been utilized where bulk donor derived NK cell infusions after haploidentical transplantation have shown early clinical efficacy [51]. More recently human NK cells have been used to generate CAR cells directed against CS-1 as potent effectors against myeloma in vitro and in mouse models [20]. Perhaps most fascinating strategy for the utilization of allogeneic lymphocyte populations for cancer immunotherapy lie in utilizing third party donors as a healthy source of bulk lymphocytes from which specific lymphocytes populations of interest may be derived, expanded and/or genetically modified. This strategy has been most successfully utilized in the setting of viral antigen associated tumors, more specifically those related to EBV reactivation [52,53]. Significant efficacy has been demonstrated post AlloSCT for the therapy of Current Opinion in Immunology 2014, 27:38–45

immunosuppression related EBV malignancies or in the setting of primary EBV positive malignancies, which have relapsed despite AlloSCT [54]. This concept has been further expanded to utilize partially matched third party donors as a source of cells to generate antigen specific T-cells for the therapy of EBV associated lymphoma [55,56] and is of increasing interesting application in the setting of viral specific T-cell therapy for patients with viral reactivation in the immunosuppressed or T-cell depleted post-transplant setting [57]. This third-party approach has shown promise in clinical trials with overall response rates of approximately 60%, which offers a therapeutic option when the donor is either unavailable or is EBV seronegative. It is likely that with the combination of CAR genetic engineering, generation of tumor antigen specific T-cell populations and potentially combination therapies with check point blockade inhibitors, that there will be an increasing application of third party allogeneic lymphoid populations for patients with either high risk of relapse or frank relapse of disease following AlloSCT.

Allogeneic donors as a source of other immunomodulatory cell therapies The lessons learned from the widespread practice of AlloSCT for haematologic malignancy has also opened the door for cellular therapies using allogeneic donors as a source of cell products to further improve outcomes. Whilst these are not directly anti-tumor immunotherapies, they provide an opportunity to ameliorate the major limitations of AlloSCT, namely GVHD and impaired graft function, and as a consequence enhance the safety of AlloSCT as an anti-cancer therapy. Allogeneic stem cell donors including the donation of newborn umbilical blood is a rich source of cellular products for immunomodulation. Included in these cell types are either naturally occurring or culture expanded, induced regulatory T-cell populations, regulatory NK and NKT cell populations and perhaps with the most direct impact, a source of mesenchymal stromal cells which can be utilized for pre-transplant expansion of stem cell populations thereby enhancing the pool of available stem cell donors for patients who require AlloSCT [58]. As increasing clinical familiarity of alternative donor sources increases, there has been a development of even more novel approaches with respect to AlloSCT including combining the bone marrow repopulating potency of haploidentical transplantation with a long term immune reconstituting power of cord blood transplantation thereby limiting the risks associated with either stem cell source alone and compounding the benefits of these two approaches [59].

Conclusion Allogeneic stem cell transplantation using related or unrelated adult donors, umbilical cord blood units, www.sciencedirect.com

Allogeneic cancer immunotherapy Parmar and Ritchie 43

matched or partially mismatched or even haplo-identical to the recipient following ablative, reduced intensity or non-ablative conditioning provides for a staggering range of potential bone marrow transplant options available in current clinical practice. To these transplant approaches additional immuno-modulatory therapies can now added including bulk or purified T cell or NK cell subsets, regulatory T cells and immune-modifying drug treatments. Collectively these complex therapies provide a potent array of cancer-beating immunotherapeutic approaches, the application and study of which have taught us key lessons in understanding anti-cancer immunology.

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EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood 2012, 119:2644-2656. 55. Haque T, Wilkie GM, Taylor C, Amlot PL, Murad P, Iley A et al.: Treatment of Epstein-Barr-virus-positive posttransplantation lymphoproliferative disease with partly HLAmatched allogeneic cytotoxic T cells. Lancet 2002, 360:436-442. 56. Barker JN, Doubrovina E, Sauter C, Jaroscak JJ, Perales MA, Doubrovin M et al.: Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes. Blood 2010, 116:5045-5049. 57. Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P, Antin JH et al.: Multicenter study of banked third-party

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