Regression of Metastatic Renal-Cell Carcinoma after Nonmyeloablative Allogeneic Peripheral-Blood Stem-Cell Transplantation

Childs, Richard W.; Chernoff, Allen; Contentin, Nathalie; Bahceci, Erkut; Schrump, David S.; Leitman, Susan F.; Read, Elizabeth J.; Tisdale, John F.; Dunbar, Cynthia E.; Linehan, W. Marston; Young, Neal S.; Clave, Emmanuel; Epperson, Diane E.; Mayo, Virginia; Barrett, A. John

doi:10.1056/nejm200009143431101

Cited by 929 publications

(599 citation statements)

References 25 publications

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“…Alternative new immunotherapies for RCC are expected because of its relatively high immunogenicity, 24 -26 and good results have been reported for several clinical trials. 27,28 In particular, an immunological approach using induction of CTL, has been considered promising, because the expression of human leukocyte antigen class I molecules is preserved at a high rate in RCC. 29,30 Vaccination with cytokine gene -transfected tumor cells has been reported to be effective for inducing CTL against unknown tumor antigens in animal models 31,32 and already applied to human cancer as an autologous vaccine.…”

Section: Cancer Gene Therapymentioning

confidence: 99%

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

et al. 2002

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We studied interleukin ( IL ) -12 gene therapy using a gene gun as a new autologous vaccination strategy for cancer. In the first experiment, BALB / c mice were inoculated with syngeneic murine renal cancer cells ( Renca ) intradermally in the abdomen. This was followed by an injection of IL -12 expression plasmid using the gene gun. About 40% of the mice exhibited rejection of the tumor after the treatment and these mice also acquired immunological resistance against a secondary challenge with Renca cells. Based on these results, we examined whether antitumor activity can be potentiated when mice undergo combination treatment with intradermal inoculation of irradiated Renca cells and transfection with IL -12 gene. Inoculation of irradiated Renca cells alone was partially effective in inducing antitumor immunity, whereas the combined treatment remarkably intensified this effect. Moreover, this combined treatment inhibited tumor establishment and enhanced survival of the mice with tumor infiltration by CD4 + and CD8 + T cells, even when the treatment was started after tumor -implantation at a distant site. This antitumor effect was antigen specific and we confirmed the induction of antitumor cytotoxic T cells by this treatment. These results show that local cutaneous transfer of IL -12 expression plasmid using gene gun technology enhances systemic and specific antitumor immunity primed by irradiated tumor cells.

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Section: Cancer Gene Therapymentioning

confidence: 99%

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

et al. 2002

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“…Nevertheless, both interferon alpha and IL-2 are toxic, and the large majority of individuals who receive them derive no benefit. Efforts to develop more sophisticated immunotherapy platforms for this disease, including newer cytokine therapy (Alatrash et al, 2004), vaccine therapy (Uemura et al, 2006;Ernstoff et al, 2007), and nonmyeloablative transplantation (Childs et al, 2000;Artz et al, 2004;Rini et al, 2006), have been reported. Although these approaches have demonstrated tantalising indications of efficacy in a small group of individuals, they have not reached the threshold of therapeutic efficacy or safety.…”

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confidence: 99%

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

et al. 2008

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The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 × 10 6 U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.

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“…In addition, allogenic hematopoietic stem cell transplantation represents the most potent form of cancer immunotherapy available for advanced hematological malignancies. Recently, nonmyeloablative allogeneic stem cell transplantation (NST) has been actively explored in patients with solid tumors, such as renal cell carcinoma, with well-documented examples of dramatic regression of metastatic disease [35]. Allogeneic stem cell transplant requires optimal immune reconstitution, which maximizes the graft-versus-leukemia or graftversus-tumor (GVT) reaction while minimizing graftversus-host disease [36].…”

Section: Discussionmentioning

confidence: 99%

Anti‐tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution

Urba

Liu

et al. 2003

Eur J Immunol

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To test whether homeostasis-driven T cell proliferation in reconstituted lymphodepleted hosts would improve the therapeutic efficacy of tumor vaccines, normal mice and reconstituted lymphopenic mice (RLM; C57BL/6 mice rendered lymphopenic with sublethal totalbody irradiation and reconstituted with naive splenocytes) were used in the vaccination and challenge experiments with weakly immunogenic F10 melanoma cells. Only limited protection was observed in vaccinated normal mice (16.7%), whereas significantly greater protection was induced in vaccinated RLM (63.2%). Protective immunity in RLM depended on CD8 T cells. Following vaccination, a significant increase in the percentage of CD44 hi CD62L lo T cells was detected in the tumor vaccine-draining lymph node (TVDLN) of vaccinated RLM compared to that of vaccinated normal mice. After in vitro stimulation, effector T cells generated from TVDLN of vaccinated RLM produced more IFN-+ than T cells from vaccinated normal mice, and contained more melanoma-specific T cells, as assessed by ELISA and intracellular cytokine staining. This study suggests that vaccination of reconstituted lymphopenic hosts could elicit superior anti-tumor immunity compared to normal hosts, highlighting the potential clinical benefit of performing tumor vaccination during immune reconstitution.

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Regression of Metastatic Renal-Cell Carcinoma after Nonmyeloablative Allogeneic Peripheral-Blood Stem-Cell Transplantation

Abstract: Nonmyeloablative allogeneic stem-cell transplantation can induce sustained regression of metastatic renal-cell carcinoma in patients who have had no response to conventional immunotherapy.

Cited by 929 publications

References 25 publications

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

Anti‐tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution

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