Combining allogeneic immunotherapy with an mTOR inhibitor for advanced renal cell carcinoma

Tykodi, Scott S.; Voong, Lilien N.; Warren, Edus H.

doi:10.1038/bmt.2009.338

Cited by 4 publications

(5 citation statements)

References 9 publications

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“…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].…”

Section: A Paradigm Change For Primary Therapy Of Metastatic Rccmentioning

confidence: 84%

“…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.…”

Section: Expert Opinionmentioning

confidence: 99%

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Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after

Tykodi

Sandmaier

Warren

et al. 2011

Expert Opinion on Biological Therapy

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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.

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Section: A Paradigm Change For Primary Therapy Of Metastatic Rccmentioning

confidence: 84%

Section: Expert Opinionmentioning

confidence: 99%

Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after

Tykodi

Sandmaier

Warren

et al. 2011

Expert Opinion on Biological Therapy

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“…27 Interestingly, the combination adoptive immunotherapy with other modalities such as mTOR inhibitors could increase the efficacy of the therapy in patients with advanced RCC. [28][29][30] However, there will be a higher GVHD risk after donor leukocyte infusion infusion in haploidentical setting and may not result in increased GVL activity as shown in some experimental models. 31 We conclude that problems including organ toxicity, GVHD, graft manipulation to introduce haplo-SCT to the clinic for RCC can be evaluated with well-designed clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma

Budak‐Alpdoğan

Sauter

Bailey

et al. 2013

Bone Marrow Transplant

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Allogeneic hematopoietic SCT (HSCT) has been shown to be an effective treatment option for advanced renal cell cancer (RCC). However, tumor resistance/relapse remains as the main post transplant issue. Therefore, enhancing graft-versus-tumor (GVT) activity without increasing GVHD is critical for improving the outcome of HSCT. We explored the GVT effect of haploidentical-SCT (haplo-SCT) against RCC in murine models. Lethally irradiated CB6F1 (H2K b/d ) recipients were transplanted with T-cell-depleted BM cells from B6CBAF1 (H2K b/k ) mice. Haplo-SCT combined with a low-dose haploidentical (HI) T-cell infusion (1 Â 10 5 ) successfully provided GVT activity without incurring GVHD. This effect elicited murine RCC growth control and consequently displayed a comparative survival advantage of haplo-SCT recipients when compared with MHC-matched (B6D2F1-CB6F1) and parent-F1 (B6-CB6F1) transplant recipients. Recipients of haplo-SCT had an increase in donor-derived splenic T-cell numbers, T-cell proliferation and IFN-g-secreting donor-derived T-cells, a critical aspect for anti-tumor activity. The splenocytes from B6CBAF1 mice had a higher cytotoxicity against RENCA cells than the splenocytes from B6 and B6D2F1 donors after tumor challenge. These findings suggest that haplo-SCT might be an innovative immunotherapeutic platform for solid tumors, particularly for renal cell carcinoma. Keywords: renal cell cancer; animal models; graft-versus-tumor effect; GVHD; haploidentical hematopoietic SCT INTRODUCTION Allogeneic hematopoietic SCT (HSCT) has been successfully used for treatment of hematological malignancies. However, this approach has not been used for patients with solid tumors, even for tumor types where immune modulatory treatments are widely used. Anti-tumor or graft-versus-tumor (GVT) effects of the graft contribute to the elimination of the residual tumor cells in certain types of malignancies. For the most part, the transplant community does not consider patients with solid tumors to be good candidates for allogeneic HSCT due to transplant-related mortality and late reconstitution of immune competency. However, pioneering studies suggest that non-myeloablative allogeneic HSCT for advanced renal cell cancer (RCC) might induce sustained regression of metastatic RCC in patients who have failed conventional therapies. [1][2][3][4][5] Seventy-four patients with advanced RCC underwent allogeneic HSCT following non-myeloablative conditioning, and 39% of the patients were responsive, including 9.5% of patients that underwent a CR. 5 The median tumor response occurred at 133 days after allogeneic HSCT and there were detectable RCC-reactive CD8 T-cells in responsive patients. 5 The onset of RCC regression after non-myeloablative HSCT is delayed by several months, which suggests that GVT activity of MHC-matched HSCT is a slow process and may not be sufficient to control aggressive disease. In a European study, OS was found to be 30% at 2 years after HSCT. 3 However, CALGB data did not support these observations and did not re...

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“…5 In addition, data suggest that rapamycin and related agents relatively increase Tregs and may be beneficial to the protection of the host without compromising the antitumor activity of the transplant. 6 Now Tykodi et al 1 add the useful information that in vitro treatment of RCC tumor cells with cytostatic concentrations of rapamycin does not interfere with CTL recognition of HA-1 expressed by RCC tumor or other characterized minor H Ags, suggesting that mammalian target of rapamycin inhibition is permissive for a sustained graft-vs-tumor activity at the target cell level for RCC tumors.…”

mentioning

confidence: 99%

“…We thank Tykodi et al 1 for their thoughtful comments on the potential advantages of combining adoptive allogeneic immunotherapy with mammalian target of rapamycin inhibitors for the treatment of advanced renal cell carcinoma. In 2008 we initiated an IRB-approved prospective, single-arm phase II study (nicknamed AlloTOR), which combines a reduced-intensity conditioning, HLA-identical sibling donor allograft with post transplant temsirolimus for patients with advanced renal cell carcinoma (RCC) who have failed a thyrosine kinase inhibitor-based therapy.…”

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confidence: 99%

Combining allografting with mTOR inhibitors for metastatic renal cell cancer

Bregni

Vitali

Peccatori

2011

Bone Marrow Transplant

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We thank Tykodi et al. 1 for their thoughtful comments on the potential advantages of combining adoptive allogeneic immunotherapy with mammalian target of rapamycin inhibitors for the treatment of advanced renal cell carcinoma. In 2008 we initiated an IRB-approved prospective, single-arm phase II study (nicknamed AlloTOR), which combines a reduced-intensity conditioning, HLA-identical sibling donor allograft with post transplant temsirolimus for patients with advanced renal cell carcinoma (RCC) who have failed a thyrosine kinase inhibitor-based therapy. The clinical rationale of this approach relies on the long-term results of allograft in metastatic RCC, 2-4 and on the encouraging results of second-or third-line temsirolimus in patients resistant/ refractory to thyrosine kinase inhibitor therapy. 5 In addition, data suggest that rapamycin and related agents relatively increase Tregs and may be beneficial to the protection of the host without compromising the antitumor activity of the transplant. 6 Now Tykodi et al. 1 add the useful information that in vitro treatment of RCC tumor cells with cytostatic concentrations of rapamycin does not interfere with CTL recognition of HA-1 expressed by RCC tumor or other characterized minor H Ags, suggesting that mammalian target of rapamycin inhibition is permissive for a sustained graft-vs-tumor activity at the target cell level for RCC tumors.This approach has robust biological and clinical rationale, but is however difficult to pursue in the actual clinical scenario. In these 2 years we have screened five patients with tyrosine kinase inhibitor-resistant/refractory RCC, potentially eligible for the protocol: three did not have a donor, and two had an HLA-identical sibling. One was not eligible for the protocol, and one refused to undergo the transplant. No patient has actually received the treatment as per protocol. We hope that, given the new and exciting results of immunotherapy in genitourinary cancer, 7 adoptive immunotherapy will also find its right place in the treatment of advanced RCC. Conflict of interestThe authors declare no conflict of interest.

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Combining allogeneic immunotherapy with an mTOR inhibitor for advanced renal cell carcinoma

Cited by 4 publications

References 9 publications

Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after

Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after

Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma

Combining allografting with mTOR inhibitors for metastatic renal cell cancer

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