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Immunotherapy of cancer: anti-CTLA-4 antibody development


Immunotherapy of cancer has a history full of important discoveries that goes back to the late nineteenth century, when William B. Coley observed tumor regressions following the injection of a bacterial broth also known as Coley’s toxins into malignant lesions.
This was followed by a series of discoveries but also draw-backs that have led to marked fluctuations in attitude toward cancer immunotherapy.

Cancer immunotherapies, ranging from monoclonal antibodies to complex cellular vaccines, have long been considered as promising, and are expected to provide clinical benefit with focused or minimal toxicities. The fact that they have not yet delivered on that promise may be due to the incomplete scientific understanding of tumor immunology on one hand and the use of conventional development plans as defined for the distinctly different but more familiar chemotherapeutic agents on the other hand. Thus, some immunotherapy failures can probably be explained by their lack of efficacy, while others may be due to an inadequate approach to their development.

In the last three years the field, for the first time, saw the clinical proof of success for cancer immunotherapies achieved in controlled randomized phase III trials meeting primary survival endpoints: the first regulatory approvals of a therapeutic cancer vaccine, Sipuleucel-T ( Provenge ) for hormone-refractory prostate cancer, and for the T-cell potentiating monoclonal antibody anti-CTLA-4 ( Ipilimumab; Yervoy ).
With these historic milestones reached in two unrelated tumor entities and two distinct agents, immunotherapy is finding entry to the landscape of prescription medicines in oncology next to the existing approaches of chemotherapy, small molecule targeted therapies, radiation and surgery.

The importance of the new immunotherapy paradigm is illustrated through the example of anti-CTLA-4 antibody development.
Clinical investigation of anti-CTLA-4 antibodies started at the biotechnology company Medarex in 2000 with phase 1 and 2 trials indicating close to 10% response rates as a signal of clinical activity in patients with advanced melanoma.
Interest from big pharma for developing anti-CTLA-4 blocking antibodies led to independent licensing deals with Pfizer and Bristol-Myers Squibb ( BMS ) for isoforms of the antibody and two parallel development programs in advanced melanoma with Tremelimumab ( Pfizer ) and Ipilimumab ( BMS ), respectively.
Both programs initially used chemotherapy criteria to guide their development choices. As per its design, the Tremelimumab program conducted an early interim analysis with conventional futility criteria for survival in its phase 3 study and could not observe a survival improvement. Consequently, the phase 3 study was terminated for futility as per Data Monitoring Committee recommendations. Two years later, extended follow-up on the study population revealed a separation of survival curves.

The scientific approach for Ipilimumab evolved and led to the change of the primary endpoint for both of its phase 3 studies in advanced melanoma to overall survival with no early interim analyses, which could mislead the survival assessment. The final analysis of survival of two phase 3 studies demonstrated improved survival ( hazard ratio, HR=0.66 and HR=0.72, respectively ) and supported the approval for patients with pretreated metastatic melanoma.

Based on the understanding of immunotherapy development BMS acquired Medarex in 2009 in a transaction valued $2.4 billion and is now developing a pipeline of immuno-oncology agents resulting from the acquisition.

The development paths for Ipilimumab and Tremelimumab and their respective results illustrate the importance of the science-driven clinical development paradigm for immunotherapies and of collaboration across various constituents to direct scientific progress.
These observations also suggest that the prospective application of the new paradigm may help avoid critical pitfalls for future immunotherapy programs. ( Xagena )

Hoos A, Britten C, Oncoimmunology 2012; 1: 334–339

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