Combining allografting with mTOR inhibitors for metastatic renal cell cancer

Abstract

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.

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

“…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.…”