Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206

Ribas, Antoni; Camacho, Luis H.; López-Berestein, Gabriel; Pavlov, Dmitri; Bulanhagui, C. A.; Millham, Robert; Comı́n-Anduix, Begoña; Reuben, James M.; Seja, Elizabeth; Parker, Charla A.; Sharma, Amarnath; Glaspy, John A.; Gómez-Navarro, Jesús

doi:10.1200/jco.2005.01.109

Cited by 549 publications

(432 citation statements)

References 29 publications

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“…Rates of grade 3 or higher diarrhea/colitis in this study were similar to the rates reported in the phase II study of single-agent tremelimumab at a higher dose (15mg/kg). Interestingly, 10mg/kg was the MTD identified in the first-in-human study of tremelimumab 9 and ultimately this dose was found to be more tolerable when dosed at a frequency of every 3 months. 10 We found no evidence that CP-870,893 aggravated tremelimumab-associated toxicity or vice versa, nor did a new spectrum of autoimmunity emerge.…”

Section: Discussionmentioning

confidence: 99%

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.

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Section: Discussionmentioning

confidence: 99%

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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“…Limited pre-clinical studies have suggested that aging may result in an imbalanced immune system (between native and adaptive arms) that favors antitumor activity. 29 Clinical trials have confirmed that elderly patients with advanced melanoma do respond to immunotherapies such as tumor vaccines, and anti-CTLA4 therapy 5,30,31 Ipilimumab has shown an improvement in overall survival (OS) in advanced melanoma compared to an experimental peptide vaccine 5 and a 5-y OS of »20%. 32 One subgroup analysis suggested equivalent benefits in patients >70 y.…”

Section: Discussionmentioning

confidence: 99%

Responses to immune checkpoint inhibitors in nonagenarians

et al. 2016

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The incidence of melanoma continues to rise with the most rapid increase seen in the elderly population. Historically, elderly patients with advanced melanoma have had dismal clinical outcomes, in part, due to distinct tumor biology, and often ineligibility for effective therapies during their development. In addition, due to relatively few geriatric patients being accrued to clinical trials of novel immunotherapeutics, there is a paucity of data regarding their safety and efficacy. Herein, we present the clinical course of three consecutive nonagenarians ( 90 y old) with metastatic melanoma, who were treated with single-agent or combination immune checkpoint inhibitors. Two patients experienced complete or partial responses with acceptable safety profiles, and one other tolerated therapy well although a significant response was not noted. These cases suggest that with close monitoring, even very elderly patients with advanced cancers and acceptable performance status may tolerate and benefit from immune checkpoint inhibitors.

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“…They are also being used in combination with tumour vaccines (peptides) [9,10] or various forms of chemotherapy (http://clinicaltrials.gov/). Importantly, tumour responses often develop over an extended period of weeks or months and tend to correlate with autoimmune manifestations and systemic inflammation, seen in at least a third of patients [11,12].…”

Section: Introductionmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD81 T cells but produced fewer IFN-c-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.

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Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206

Abstract: CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.

Cited by 549 publications

References 29 publications

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Responses to immune checkpoint inhibitors in nonagenarians

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

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