Allogeneic Hematopoietic Cell Transplantation for Renal Cell Carcinoma: Ten Years After

Abstract

Introduction

The first series of patients with metastatic renal cell carcinoma (RCC) treated by nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) was reported in 2000 and demonstrated an allogeneic graft-versus-tumor (GVT) effect that encouraged further investigation of this approach. However, the past 10 years have also witnessed profound changes in the medical management of metastatic RCC with the introduction of targeted therapies directed against vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) signaling pathways creating uncertainty about a continued role for allogeneic HCT in the treatment of RCC.

Areas covered

Twenty-one published reports describing clinical outcomes for 398 patients with metastatic RCC treated by allogeneic HCT compiled herein provide a composite overview of the world wide experience for key efficacy and toxicity outcomes. Review of correlative studies that identify donor-derived T cells as mediators of RCC-specific GVT effects offers insight into both the potential as well as the technical barriers to the delivery of antigen-specific posttransplant cellular therapy or vaccination designed to augment the allogeneic GVT effect.

Expert opinion

The future development of nonmyeloablative allogeneic HCT for metastatic RCC will require novel treatment protocols designed to augment and sustain posttransplant GVT effects against RCC to generate renewed enthusiasm for this approach.

1. Introduction

Renal cell carcinoma (RCC) accounts for 3-4% of new cancer diagnoses in the United States and the majority of patients either present with metastatic disease or relapse following surgical resection [1, 2]. Systemic chemotherapy has minimal activity against metastatic RCC and single- or multi-agent regimens have never been established as a recognized standard approach for this disease [3]. In contrast, RCC has proven to be sensitive to immunotherapies. With the commercial availability of interferon-alpha after 1986 and FDA approval of interleukin-2 for treatment of RCC in 1992, front-line treatment of metastatic RCC with systemic cytokine therapies was widely adopted and demonstrated incremental benefit in overall patient survival despite modest objective response rates around 20% [4-6]. Of great interest, 5 to 7% of patients responding to high dose IL-2 have been observed to achieve durable complete remission of their disease [7]. The mechanism for the anti-tumor effect of cytokine therapies for RCC remains incompletely defined. However, both animal models and human studies have suggested that cytokine therapies could augment host cellular immune responses capable of recognizing RCC tumor [8-13]. The widespread application of immune therapies for RCC with occasional striking success has provided strong encouragement for the development of novel immunologic approaches to treatment including allogeneic hematopoietic cell transplantation (HCT).

The retrospective analysis of leukemic patients treated by myeloablative allogeneic HCT observed that the risk of relapse was lower in patients who developed acute and/or chronic graft-versus-host disease (GVHD), lower in recipients of allogeneic compared with syngeneic marrow, and higher in recipients of T cell-depleted compared with unmodified marrow [14]. Such data first suggested that a graft-versus-tumor (GVT) effect mediated by T lymphocytes derived from the transplant donor was a key component of the anti-tumor properties of allogeneic HCT. Direct evidence for a role for donor T cells in the GVT effect was further provided by studies of donor lymphocyte infusions (DLI) to treat posttransplant relapse that demonstrated anti-leukemic activity in the absence of any conditioning chemotherapies [15, 16].

Recognition that the GVT effect made a major contribution to eradicating leukemia following conventional myeloablative allogeneic HCT provided the conceptual foundation for the development of reduced-intensity, nonmyeloablative conditioning regimens causing little organ toxicity, but suppressing the recipient immune system sufficiently to allow the engraftment of donor cells [17]. The demonstration that nonmyeloablative allogeneic HCT could be successfully applied to the treatment of hematologic malignancies encouraged the examination of nonmyeloablative allogeneic HCT as a novel form of immunotherapy for tumors not historically treated by allogeneic HCT including advanced RCC.

In 2000, Childs and coworkers at the National Cancer Institute (NCI) in Bethesda, Maryland, reported the first case series of 19 patients with metastatic RCC who had failed prior cytokine (17/19) or other therapies and were treated by nonmyeloablative conditioning therapy with cyclophosphamide and fludarabine followed by allogeneic peripheral blood stem cell transplantation received from an HLA-matched (N=17) or single antigen mismatched (N=2) sibling donor. Cyclosporine was used for posttransplant immunosuppression. All patients achieved donor engraftment of both myeloid and lymphoid lineages. Of great interest, objective responses were observed in 10/19 (53%) patients and included 3 complete responders. These observations first suggested that advanced RCC was sensitive to an allogeneic GVT effect. Toxicities were comparable to outcomes reported in patients with hematologic malignancies treated by similar transplant protocols and included two treatment-related deaths (11%), and the development of acute (grade II to IV) or chronic graft-versus-host disease in 53% and 21% of patients, respectively [18].

2. Clinical Outcomes of Allogeneic HCT for RCC

Following the initial report by Childs and coworkers, nonmyeloablative allogeneic HCT treatment protocols for advanced RCC have been further examined by investigators at several US and international transplant centers. Twenty-one reports describing clinical outcomes for 17 separate case series of >3 RCC patients treated by nonmyeloablative conditioning and allogeneic HCT were identified and summarized in Table 1 [18-38]. Confirmatory evidence for an allogeneic GVT effect against advanced RCC was reported in 13 of the 17 case series. Responses were observed following transplants received from sibling donors, as well as from HLA-identical unrelated donors, or from unrelated cord blood stem cells [25, 38]. However, in contrast to a 53% overall response rate first reported by Childs and co-workers [18], the response rates among the 17 case series were highly variable (range 0 to 57%) with a median response rate of only 14% (Table 1). Similarly, the aggregate response rate for 398 patients compiled from 21 reports listed in Table 1 (allowing that some patients could be counted twice within the EBMT retrospective analysis of 124 patients [36] and smaller reported case series from European centers) was 89/398, or 22%; also substantially lower than observed by Childs and coworkers. In addition, complete responses were rare with most responding patients achieving only transient partial remissions and suffering subsequent disease progression. Many of the objective responses also occurred only after the application of posttransplant therapies to manage disease progression. For example, in 6 of 13 reports describing objective responses of metastatic RCC following allogeneic HCT, the response(s) of one or more patients followed the application of posttransplant DLI or interferon (IFN)-alfa (Table 1) [18, 23, 25, 26, 29, 33, 36]. Treatment by nonmyeloablative conditioning and allogeneic HCT also exposed patients to morbidity and mortality risks inherent to this style of adoptive immunotherapy. Transplant-related deaths were reported in 14 of the 17 series (range 0-43%) with a median rate of 14%. Additionally, rates of acute and chronic GVHD (median of 44% and 47% respectively) generally reflected treatment-associated norms established by the broader use of nonmyeloablative conditioning and allogeneic HCT for patients with hematologic malignancies [39].

Table 1.

Published Series of Allogeneic Hematopoieic Cell Transplantation for RCC^§

Reference	No. of Patients	Conditioning	GVHD† Prophylaxis	% of Patients				Response post DLI / IFN
				aGVHD (II-IV)	cGVHD	TRM	Response (CR+PR)
US Centers
Childs et al. (2000), Takahashi et al. (2008)¶	19	Flu + Cy	CSP	53	21	11	53	yes
	74	Flu + Cy	CSP	55	47	11	39	yes
Rini et al. (2002), Artz et. al. (2005)¶	18	Flu + Cy	Tac + MMF	18	58	28	22	no
Ueno et al. (2003), Nakayama et al. (2007)¶	23	Flu + Mel	Tac + MTX	65	no data	39	26	no
Tykodi et al. (2004)	8	Flu + TBI	CSP + MMF	50	50	13	13	yes
Rini et al. (2006)	22	Flu + Cy	Tac + MTX	50	23	9	0	N/A
Peres et al. (2007)	16	Flu + Cy or Flu + TBI	CSP + MMF	44	43	13	31	yes
International Centers
Pedrazzoli et al. (2002)	7	Flu + Cy	CSP + MTX	0*	no data	29*	0*	N/A
Bregni et al. (2002), Bregni et al. (2009)¶	25	TT + Flu + Cy	CSP + MTX or sirolimus	48	36	24	20	yes
Hentschke et al. (2003)	10	Flu + TBI +/− ATG	CSP + MMF	50	43	30	0	N/A
Blaise et al. (2004)	25	Flu + Bu + ATG	CSP	42	44	9	8*	no
Nakagawa et al. (2004)	9	Flu/Cla + Bu + ATG	CSP	44	50	0	11	no
Massenkeil et al. (2004)	7	Flu + Cy + ATG	CSP +/− MMF	29	67	14	29	yes
Rzepecki et al. (2005)	5	Flu + Cy	CSP + MTX	60	75	0	0	N/A
Busca et al. (2006)	7	Flu + TBI	CSP + MMF	29*	67*	0*	14*	no
Barkholt et al. (2006) ¶	124	Flu + variable	CSP +/− variable	39	40	16	29¥	yes
Yun et al. (2007)	11	Flu + Cy/Mel/Bu +/− ATG	CSP +/− MTX	30	86	27	9	no
Ishiyama et al. (2009)	7	Flu + Cy/Bu +/− TBI +/− ATG	CSP or Tac	57	43	43	57	no

Notes:

^§Published series with > 3 patients and reported in English are listed.

^†Abbreviations: GVHD=graft versus host disease; a=acute; c=chronic; TRM=treatment related mortality; CR=complete response; PR=partial response; DLI=donor lymphocyte infusion; IFN=interferon alpha; Flu=fludarabine; Cy=cyclophosphamide; CSP=cyclosporine; Tac=tacrolimus; MMF=mycophenylate mofetil; Mel=melphalan; MTX=methotrexate; TBI=total body irradiation; ATG=anti-thymocyte globulin; Cla=cladribine; N/A=not applicable.

^¶Reference includes previously reported patients.

^*Percentages for RCC subset of patients.

^¥Response rate calculated for 98/124 patients survivng > 90 days posttransplant.

2.1 Prognostic Factors

Based on the initial evidence for an allogeneic GVT effect against metastatic RCC from single institution case series, a multi-institutional phase II study led by the Cancer and Leukemia Group B (CALGB) cooperative group was designed to evaluate the feasibility and toxicity of this approach. Between 2002 and 2004, 22 patients were treated at 14 institutions with no objective responses observed. The study was closed to further accrual and the results were reported in 2006 [24]. Retrospective critique of this trial noted a very short median progression free survival (3.0 months) and overall patient survival (5.5 months) that may not have permitted sufficient time to observe the development of a GVT effect, which is often delayed in onset by several months from the start of the transplant [26, 36, 40]. In addition, the infrequent use of posttransplant DLI or IFN for management of disease progression (2 of 22 patients) may also have contributed to the lack of beneficial clinical effect observed. The disappointing results of the CALGB trial (and other smaller series that failed to observe tumor responses) called attention to the heterogeneity of response rates between case series for RCC patients and encouraged retrospective analyses of patient-specific clinical factors associated with tumor response or overall survival that might be used prospectively to select RCC patients more likely to benefit from allogeneic HCT.

Barkholt and co-workers, on behalf of the French Immunotherapy and Cancer (ITAC) Group and European Group for Blood and Marrow Transplantation (EBMT) Solid Tumor Working Party, reported the largest retrospective study conducted thus far of 124 RCC patients treated by nonmyeloablative allogeneic HCT performed at 21 European centers. In multivariate analysis, this study identified factors associated with tumor response or overall patient survival. Factors associated with response included a time period of less than 1 year from diagnosis of RCC to allogeneic HCT, transplantation from an HLA-mismatched donor, and acute GVHD. The factors associated with improved survival following allogeneic HCT included chronic GVHD, use of DLI, a Karnofsky score ≥ 80%, and less than three sites of metastases [36]. In a separate analysis of clinical features associated with treatment outcome, Peccatori and co-workers identified 70 RCC patients treated by nonmyeloablative allogeneic HCT at 9 EBMT centers. In multivariate analysis, Karnofsky performance status, C-reactive protein (CRP) level, and lactate dehydrogenase (LDH) level were shown to segregate patients into high-risk and low-risk cohorts with markedly different median survival of 3.5 months versus 23 months respectively [41]. From analysis of the largest single-institution series of 74 RCC patients treated by nonmyeloablative allogeneic HCT, Takahashi and co-workers noted a statistically significant difference in response rate for patients with clear cell RCC versus other histologies (48% versus 0% RR, P=0.0018) [26]. Finally, retrospective analyses of smaller case series also reported an association with the number of CD34⁺ transfused cells, disease status at day +90, and hematocrit level with overall patient survival [22, 29].

The retrospectively defined clinical variables associated with tumor regression or patient survival that might be used prospectively to select RCC patients more likely to benefit from allogeneic HCT (a time period of less than 1 year from diagnosis of RCC to treatment, Karnofsky score, less than three sites of metastases, CRP level, LDH level, hematocrit level, and clear cell histology) largely corresponded to previously identified RCC-specific prognostic factors, and were therefore unlikely to represent treatment-specific predictive markers. Investigators at Memorial Sloan Kettering Cancer Center (MSKCC) and other centers used clinical factors that included performance status, serum hemoglobin, calcium, LDH, time from initial diagnosis to systemic treatment, and number of sites of metastases to stratify RCC patients into favorable, intermediate, or poor prognostic groups [42, 43]. Thus, RCC patients corresponding to the previously defined favorable risk group appeared more likely to respond to allogeneic HCT. The sensitivity of clear cell versus other histologic subtypes of RCC to an allogeneic GVT effect was also an association with immunotherapy previously observed for RCC tumors treated with systemic cytokines [44, 45].

2.2 Mechanism of the GVT Effect

Insight into the mechanism of a posttransplant RCC-specific GVT effect might also identify strategies for augmenting the anti-tumor activity. Several lines of evidence suggested a significant role for donor T cells mediating GVT effects following allogeneic HCT for RCC. The conditioning regimens employed for nonmyeloablative HCT lacked anti-tumor activity and the onset of RCC regression following allogeneic HCT was often delayed for several months. For example, the median time to response observed in the two largest case series of RCC patients treated by allogeneic HCT was 150 days and 133 days, respectively [26, 36]. The onset of tumor regression often corresponded to the development of complete donor chimerism of CD3⁺ cells, the withdrawal of immune suppression, or followed posttransplant treatment with DLI or IFN-alfa and was associated with the development of acute GVHD [18, 36]. In addition, greater numbers of CD8⁺ T cells have been measured in the posttransplant peripheral blood of responding versus nonresponding patients [46]. Infiltration of responding tumors by donor-derived CD8⁺ T cells has also been observed [38, 47].

3. RCC-reactive T cell specificity following allogeneic HCT

Minor histocompatibility (H) antigens are MHC-associated peptides encoded by polymorphic genes that differ between allogeneic transplant donor and recipient resulting in protein sequence differences that appear “foreign” to donor T lymphocytes and elicit donor T cell responses following HCT. A murine model of allogeneic graft-versus-host effects mediated by CD8⁺ T cells recognizing class I MHC-associated minor H antigens has demonstrated an important role for the presentation of minor H antigens on recipient bone marrow-derived professional antigen presenting cells (APC) [48]. This model for minor H antigen immunogenicity and the clinical observation of RCC tumor regression closely associated with the development of posttransplant GVHD [18, 36] motivated our group to investigate minor H antigen targets shared between hematopoietic and RCC target cells that could be detected in posttransplant peripheral blood samples of RCC patients treated by nonmyeloablative HCT at our institution. Our group demonstrated that tumor-reactive CD8⁺ T cell clones recognizing minor H antigens expressed by RCC tumor cells could be isolated from the peripheral blood of RCC patients treated by nonmyeloablative allogeneic HCT. An RCC-reactive CD8⁺ CTL clone isolated from a patient who experienced a partial regression (PR) of bulky metastatic RCC was specific for the previously characterized HLA-A2-associated HA-1 minor H antigen [23]. Encoded by the HMHA1 gene located on chromosome 19p13.3, the HA-1 antigen is selectively expressed by hematopoietic cells and some solid tumors including RCC, but not by cells in other normal tissues [49-51].

Our group subsequently identified a novel HLA-A2-associated minor H antigen expressed by RCC tumor that was encoded by an alternative open reading frame in C19orf48, a gene of unknown function located on chromosome 19q13. The C19orf48 reading frame spanning the minor H antigen peptide epitope encoded a predicted polypeptide of only 48 residues. Of interest, the C19orf48 epitope was recognized by CTL clones isolated from two different patients with metastatic RCC who experienced a PR or prolonged stable disease respectively following nonmyeloablative allogeneic HCT. However, in addition to RCC tumor cells, C19orf48 transcript was also broadly detected in normal tissues including liver and intestine that are target organs of GVHD [52].

We also evaluated four additional minor H antigens previously identified from studies of leukemic patients and encoded by the Y-chromosome gene JARID1D (SMCY), or the autosomal genes KIAA0020 (HA-8), SP110, and AKAP13 (HA-3) for their expression by RCC tumor cells and recognition by CTL clones in vitro. Each of these four minor H antigens was a constitutively expressed target for robust CTL-mediated anti-tumor effects measured by in vitro assays [S.S. Tykodi and E. H. Warren, unpublished observations]. Along with studies by others demonstrating expression of the minor H antigen encoded by P2X5 in RCC tumor cells [53], collectively these data identify seven molecularly-defined minor H antigens that have been shown to be expressed by RCC tumor cells measured by in vitro assays and that may therefore contribute to posttransplant GVT effects [23, 50-53]. The expression profile of these RCC-associated minor H antigens in nonmalignant tissues are heterogeneous and include minor H antigens broadly expressed in normal tissues (JARID1D, HA-8, HA-3, C19orf48) [49, 52, 54] as well as minor H antigens with more restricted expression (HA-1, SP110, P2X5) [49, 53, 55]. CTL targeting RCC-associated minor H antigens broadly expressed in normal tissues may contribute to posttransplant GVT effects [56] but could also account for the observation of tumor regression associated with the development of clinical GVHD [18, 36, 57, 58].

In addition to tumor-associated minor H antigen targets, both murine and human studies have also suggested a contribution of donor-derived CTL specific for nonpolymorphic tumor antigens to posttransplant GVT effects following allogeneic HCT [59, 60]. Childs and co-workers identified a nonpolymorphic RCC antigen encoded by a transcript from human endogenous retrovirus type E (HERV-E) that was recognized by an HLA-A11-restricted CD8⁺ T cell clone isolated from an RCC patient who experienced posttransplant tumor regression. Expression of the HERV-E transcript was highly tumor specific and detected in ~ 50% of cultured RCC tumor cell lines and fresh kidney tumor samples, but not in normal tissues or other non-RCC tumor cell lines [26].

Identified RCC-associated antigens with highly restricted expression in normal tissues such as HA-1 or HERV-E are of substantial interest as potential targets for posttransplant manipulation by vaccination or adoptive cellular therapy designed to augment RCC-specific GVT effects. However, such an approach would be limited to a small percent of the total RCC population due to the low phenotype frequency of the HLA-A11 restricting allele for HERV-E (14% in US Caucasians), heterogeneous expression of HERV-E and HA-1 between RCC tumors, and low probability of disparity rates for individual minor H antigens; even for minor H antigens including HA-1 that are associated with the high-frequency HLA-A2 allele (for example, patient/donor discordance rates for HA-1 are 6.6% for sibling donors or 12.0 % for unrelated donors in Caucasian populations) [23, 26, 50, 61, 62]. Thus, the practical development of posttransplant specific immunotherapy would require a substantially larger panel of RCC-associated antigens.

In vitro studies have demonstrated that mixed lymphocyte / tumor cell (MLTC) cultures using T cells isolated from healthy allogeneic donors HLA-matched to RCC tumors will elicit more vigorous CD8⁺ CTL responses than for fully autologous culture conditions [63, 64]. Forcing RCC tumor cells to serve as the APC for allogeneic CTL in MLTC culture could elicit CTL that recognize novel minor H antigens that are expressed in tumor cells but not expressed in hematopoietic or other normal tissues. Tumor-reactive T cell clones derived in this manner could direct the identification of novel RCC-associated alloantigens [65], although the successful identification of T cell antigens remains a labor intensive and technically challenging endeavor.

The most common sources of genetic variation associated with characterized human minor H antigens are non-synonymous single nucleotide polymorphisms (SNPs) that occur within protein coding sequences [66]. The use of available genetic databases to locate non-synonymous SNPs within characterized genes encoding for tumor-associated antigens with favorable expression patterns also represents a strategy to facilitate the identification of novel minor H antigen peptide sequences [67] that could be targeted therapeutically. As an example applicable to RCC, nonsynonymous SNPs are located in the RCC-associated gene encoding carbonic anhydrase IX [68] including the SNP rs2071617 causing an amino acid substitution within an immunogenic peptide sequence that can be recognized by CTL clones in association with HLA-A2 (amino acid residues 26-35; LLSLLLLMPV vs. LLSLLLLVPV) [69]. However, the presentation of these peptides by HLA-A2-positive and CAIX-expressing RCC tumors has not been established. Further, the application of such a “reverse immunology” approach to minor H antigen identification requiring assays to measure peptide binding to HLA molecules, to expand and isolate peptide-specific CTL, and ultimately to functionally assess tumor cell processing and presentation of candidate epitope sequences also presents significant technical hurdles to minor H antigen discovery.

4. A Paradigm Change for Primary Therapy of Metastatic RCC

In the 10 years since the initial study of nonmyeloablative allogeneic HCT applied to RCC, the treatment options for patients with advanced RCC have substantially evolved. Positive results from phase III clinical trials have led to regulatory approval of six new “targeted” therapeutics for advanced RCC in both the US and Europe since 2005. These include oral tyrosine kinase inhibitors (sorafenib, sunitinib, and pazopanib) [70-72] that disrupt vascular endothelial growth factor (VEGF)-receptor signaling; the intravenous VEGF-binding monoclonal antibody bevacizumab [73, 74]; or inhibitors of the mammalian target of rapamycin (mTOR) signaling pathway (temsirolimus, everolimus) [75, 76]. Therapeutic agents targeting the VEGF-signaling pathway have been studied primarily in patients with clear cell RCC tumors and prognosis corresponding to good or intermediate risk groups by MSKCC criteria therefore closely corresponding to patients retrospectively identified as more likely to respond to allogeneic HCT. The availability and rapid integration of novel targeted therapies into consensus treatment guidelines as appropriate first- and second-line treatments for metastatic RCC are certain to impact the contemporary study of allogeneic HCT for advanced RCC. A history of prior treatment with one or more targeted agents will undoubtedly supplant the past experience of front-line cytokine therapies for patients referred for treatment by allogeneic HCT.

The use of targeted therapies in combination with allogeneic HCT has also been recognized and described anecdotally [29]. A murine model demonstrating that VEGF-receptor2 blockade enhanced tumor-reactive T cell immunity in a breast carcinoma model system supports the concept of integrating anti-angiogenic therapies with immunotherapies [77]. Our group has also previously commented on the potential for mTOR inhibitors to serve a dual role in nonmyeloablative allogeneic HCT by providing posttransplant immunosuppression as well as direct anti-tumor activity against RCC delaying posttransplant tumor progression and favoring the development of a GVT effect [78]. Clinical activity of mTOR inhibitors against a variety of lymphoma subtypes has been reported, and the retrospective analysis of nonmyeloablative allogeneic HCT treatment protocols for lymphoma patients that included the posttransplant use of the mTOR inhibitor rapamycin observed improved survival for rapamycin-treated patients with a hazard ratio for disease relapse/progression of 0.5 [79]. Such data representing proof-of-concept for the combination of allogeneic immunotherapy with an mTOR inhibitor encourages a similar combinatorial approach to the treatment of metastatic RCC.

5. Expert Opinion

Ten years after Childs and coworkers published the first case series of RCC patients treated by nonmyeloablative allogeneic HCT, advanced RCC is now recognized as a solid tumor that is sensitive to an allogeneic GVT effect. However, in contrast to hematologic malignancies where the success of nonmyeloablative allogeneic HCT is typically judged by rates of sustained complete remissions, complete remissions of RCC following allogeneic HCT have been rare. The paucity of durable complete responders who might justify the exposure of RCC patients to the risks inherent in allogeneic HCT including infections and GVHD that can result in treatment associated deaths, as well as the relatively low aggregate response rate of 22% have diminished interest in the use of nonmyeloablative allogeneic HCT according to currently established treatment protocols applied to hematologic cancers. Nevertheless, the application of nonmyeloablative allogeneic HCT to metastatic RCC may remain a potential treatment option for patients. A search of the ClinicalTrials.gov database identifies five ongoing clinical trials of allogeneic HCT open to patients with metastatic RCC at both US and International transplant centers (Table 2). In addition, a recent consensus practice statement on behalf of the EBMT identifies allogeneic HCT as a “clinical option” for RCC, in contrast to all other solid tumor indications considered [80].

Table 2.

Open Studies of Allogeneic HCT for Metastatic RCC^§

ClinicalTrials.gov Identifier	Start Date	Sponsor	Conditions
NCT00003553	Jan 1999	National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD	Renal Cell Carcinoma
NCT00058825	Aug 2000	Baylor College of Medicine, Houston, TX	Renal Cell Carcinoma, Hematologic Malignancy
NCT00303719	Mar 2002	Masonic Cancer Center, University of Minnesota, Minneapolis, MN	Renal Cell Carcinoma, Hematologic Malignancy
NCT00056095	Dec 2002	Federation Nationale des Centres de Lutte Contre le Cancer, France	Renal Cell Carcinoma
NCT00923845	Mar 2008	National Cancer Institute (NCI), Bethesda, MD	Renal Cell Carcinoma

^§search terms for www.ClinicalTrials.gov] - renal cell carcinoma, renal cancer, kidney cancer, transplant, allogeneic, stem cell, open studies. [Last accessed 11 November 2010]

However, the most significant factor to influence contemporary patient accrual to available studies of allogeneic HCT for RCC is likely the development and widespread use of novel targeted therapies for the medical management of metastatic RCC. Oncology providers now have the means to offer multiple lines of therapy to RCC patients in the outpatient clinical setting thereby deferring patient referral to centers that specialize in HCT until later in their treatment course. Treatment associated toxicities can also be more easily managed by dose reduction or treatment interruption than for complications following allogeneic HCT. It is notable that the cumulative experience with allogeneic HCT for metastatic RCC reflects almost exclusively the treatment of patients following failure of front-line cytokine therapies. Therefore, the consequences of a history of prior VEGF- and/or mTOR-directed therapies on toxicities and outcomes following allogeneic HCT are unknown. Further, patients that have failed one or multiple prior lines of targeted therapies stand at high risk of rapid disease progression and clinical deterioration representing important barriers to the time requirement for patient evaluation and donor identification necessary to coordinate treatment by allogeneic HCT. It has yet to be established that patients can be effectively evaluated and enrolled onto trials of nonmyeloablative allogeneic HCT after the failure of targeted therapy.

Clinical observations and correlative laboratory studies have provided compelling evidence that the anti-tumor effect of allogeneic HCT against RCC is mediated by donor-derived T cells. Despite this insight, the mechanisms of tumor resistance to allogeneic immunotherapy are not understood. The failure of robust posttransplant RCC-reactive T cell responses to develop in some patients or phenotypic heterogeneity within RCC tumors that would predispose to immunoselection for antigen-escape tumor variants represent rational hypotheses [23 and S.S. Tykodi and E. H. Warren, unpublished observations]; however there are insufficient clinical data to draw firm conclusions. T cell responses targeting tumor-associated minor H antigens may represent uniquely potent effector cells and novel treatment strategies designed to augment T cell mediated posttransplant GVT effects without exacerbating GVHD are highly desired. Targeting RCC-associated minor H antigens with a restricted tissue distribution (HA-1, SP110, P2X5) by posttransplant adoptive T cell therapy or vaccination would be technically possible, but limited to a small fraction of potential RCC patients owing to the low population frequencies for individual minor H antigens. Thus, a sustained commitment to RCC-associated alloantigen discovery would be necessary to identify a sufficiently large panel of suitable target antigens to support pilot clinical studies of posttransplant vaccine or cellular therapies. Augmenting T cell responses against characterized nonpolymorphic and broadly shared T cell antigens with epitopes restricted by common HLA alleles such as 5T4 [81, 82], carbonic anhydrase IX [83], or MUC1 [84] would extend the possibility of delivering posttransplant specific immunotherapies to a much larger fraction of RCC patients, but T cell therapies targeting nonpolymorphic antigens could also be explored outside the context of allogeneic HCT and thereby avoiding associated toxicities.

A practical approach for the development of innovative transplant protocols in the near term would focus on the delivery of posttransplant interventions intended to augment GVT effects that could be applied to all RCC patients who would undergo allogeneic HCT. For example, a recently opened study will test the anti-tumor activity of a novel DLI product (Table 2, NCT00923845). Proof-of-concept studies in patients with hematologic malignancies combining allogeneic HCT with a targeted therapy (mTOR inhibitor) [29, 78] or with immune check point blockade (anti CTLA-4 monoclonal Ab) [85] demonstrating anti-tumor activity without excessive toxicity also represent possible approaches to extend to RCC [86]. Treatment of favorable risk RCC patients on novel clinical trials of allogeneic HCT early on in their disease course may also increase the proportion of patients able to tolerate early posttransplant disease progression allowing sufficient time for the development of posttransplant GVT effects.

In summary, in an era of expanded and competing treatment options for patients with metastatic RCC, the future development of nonmyeloablative allogeneic HCT for RCC will require novel treatment protocols that increase the likelihood for potent and sustained posttransplant GVT effects to generate renewed enthusiasm for this approach amongst patients and referring providers.

6. Article Highlights Box.

• The overall response rate calculated for 398 patients with metastatic renal cell carcinoma (RCC) treated by nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) complied from 21 published reports was 22%.

• Several lines of evidence suggest a significant role for donor T cells mediating graft-versus-tumor (GVT) effects following allogeneic HCT for RCC.

• Donor-derived cytotoxic T lymphocytes specific for RCC-associated minor histocompatibility antigens or a nonpolymorphic tumor antigen have been isolated from posttransplant peripheral blood samples obtained from RCC patients responding to nonmyeloablative allogeneic HCT.

• Novel targeted therapies directed against vascular endothelial growth factor or mammalian target of rapamycin signaling pathways have been rapidly adopted as appropriate first- and second-line treatments for metastatic RCC.

• The future development of nonmyeloablative allogeneic HCT for RCC will require novel treatment protocols that increase the likelihood for sustained posttransplant GVT effects to generate renewed enthusiasm for this approach.