Molecular-based therapies for renal cell carcinoma

Zisman, Amnon; Belldegrun, Arie S.

doi:10.1007/s11934-001-0026-8

Cited by 3 publications

(2 citation statements)

References 41 publications

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“…The 5-year survival rate for RCC patients with stage IV metastatic disease is a dismal 20% (7). Current methods for surveillance of disease progression after surgery are based entirely on clinical and pathologic indices and do not incorporate molecular markers from tumor tissues (5,8,9).…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates

et al. 2006

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Metastatic renal cell carcinoma (RCC) is an aggressive disease refractory to most existing therapeutic modalities. Identifying new markers for disease progression and drug targets for RCC will benefit this unmet medical need. We report a subset of clear cell and papillary cell RCC aberrantly expressing the lymphocyte activation marker CD70, a member of the tumor necrosis factor superfamily. Importantly, CD70 expression was found to be maintained at the metastatic sites of RCC. Anti-CD70 antibody-drug conjugates (ADC) consisting of auristatin phenylalanine phenylenediamine (AFP) or monomethyl auristatin phenylalanine (MMAF), two novel derivatives of the anti-tubulin agent auristatin, mediated potent antigendependent cytotoxicity in CD70-expressing RCC cells. Cytotoxic activity of these anti-CD70 ADCs was associated with their internalization and subcellular trafficking through the endosomal-lysosomal pathway, disruption of cellular microtubule network, and G 2 -M phase cell cycle arrest. The efficiency of drug delivery using anti-CD70 as vehicle was illustrated by the much enhanced cytotoxicity of antibodyconjugated MMAF compared with free MMAF. Hence, ADCs targeted to CD70 can selectively recognize RCC, internalize, and reach the appropriate subcellular compartment(s) for drug release and tumor cell killing. In vitro cytotoxicity of these ADCs was confirmed in xenograft models using RCC cell lines. Our findings provide evidence that CD70 is an attractive target for antibody-based therapeutics against metastatic RCC and suggest that anti-CD70 ADCs can provide a new treatment approach for advanced RCC patients who currently have no

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Section: Introductionmentioning

confidence: 99%

Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates

et al. 2006

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“…12 Metastatic RCC (MRCC) is comparatively more resistant to cytotoxic therapy and radiotherapy than other cancers. [13][14][15][16][17][18][19][20][21][22] Reviews of more than 100 trials have failed to associate a single agent with consistent levels of antitumor activity, 13,22 and to our knowledge no single-agent or combination regimen is currently accepted as the standard of care. 6,13 To our knowledge, the most effective treatment currently available is immunotherapy with interferon-␣ (IFN-␣) or interleukin-2 (IL-2), which produce an objective response in 6 -21% of patients.…”

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Phase I/II study of thalidomide in combination with interleukin‐2 in patients with metastatic renal cell carcinoma

Amato

Morgan

Rawat

2006

Cancer

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BACKGROUNDThe purpose of the study was to determine, in a Phase I/II study, the efficacy and safety profile of thalidomide with interleukin‐2 (IL‐2) in patients with metastatic renal cell carcinoma (MRCC).METHODSFifteen patients (8 of whom were previously treated) enrolled in Phase I were treated with escalating doses of oral thalidomide (200–600 mg) and a fixed dose of IL‐2 (7 mIU/m2) by subcutaneous injection. A course was 6 weeks, with the exception of Course 1, which was 7 weeks. Thirty‐seven Phase II patients who had not received prior chemotherapy or immunotherapy for renal cell carcinoma (RCC) received an initial thalidomide dose of 200 mg at Week 0, which was escalated to 400 mg after 48 hours. Subcutaneous IL‐2 was administered at the same fixed daily dose used in Phase I.RESULTSFifty‐one of 52 Phase I/II patients were evaluable. Twenty‐seven patients (52%) experienced disease control, including 4 (8%) complete responses, 15 (29%) partial responses, and 8 (15%) cases of stable disease. Disease progression was observed in 24 patients (47%). Survival in the 2 phases ranged from 4 weeks to 45.2+ months. At the time of last follow‐up, 2 of 51 patients (4%) remained on maintenance thalidomide therapy and continue to be followed. Three of the 51 patients with CRs (6%) ceased thalidomide therapy at 23–25 months and have maintained their responses to date. One complete responder was lost to follow‐up. As of January 2005, 14 of 51 patients (27%) remained alive. Toxicities were mild to moderate, including Grade 1 to 2 somnolence, constipation, neuropathy, rash, flu‐like symptoms, fluid retention, hypotension, and hypothyroidism (according to version 2.0 of National Cancer Institute Common Toxicity Criteria). In addition, two patients experienced deep venous thrombosis.CONCLUSIONSThalidomide in combination with IL‐2 is tolerable and can produce durable, active responses in patients with MRCC. To evaluate the merits of thalidomide as a valuable agent against MRCC and to more fully determine the efficacy of thalidomide/IL‐2 combination therapy, the scrutiny of Phase III testing is required. Further development of thalidomide/IL‐2 combination therapy will be the focus of this group. Cancer 2006. © 2006 American Cancer Society.

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Phase II Study of Combination Thalidomide/Interleukin-2 Therapy Plus Granulocyte Macrophage-Colony Stimulating Factor in Patients With Metastatic Renal Cell Carcinoma

Amato

Malya

Rawat

2008

American Journal of Clinical Oncology

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Thalidomide plus IL-2 in combination with GM-CSF is tolerable and produces durable responses in patients with MRCC. GM-CSF, however, did not produce a response rate superior to that reported in previous studies of combination thalidomide/IL-2 therapy. Further development of the thalidomide plus IL-2 combination therapy will address patients who have received molecular-targeted agents, such as sunitinib and sorafenib, as first- or second-line therapy.

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Molecular-based therapies for renal cell carcinoma

Cited by 3 publications

References 41 publications

Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates

Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates

Phase I/II study of thalidomide in combination with interleukin‐2 in patients with metastatic renal cell carcinoma

Phase II Study of Combination Thalidomide/Interleukin-2 Therapy Plus Granulocyte Macrophage-Colony Stimulating Factor in Patients With Metastatic Renal Cell Carcinoma

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