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Published on: February 24, 2023
Anti-CTLA4 Antibody Clinical Trials in Melanoma
1Department of Medicine, Division of Hematology/Oncology; Department Surgery, Division of Surgical Oncology; and Jonsson Comprehensive Cancer Center, University of California at Los Angeles (UCLA).
Abstract:
The cytotoxic T lymphocyte-associated protein 4 (CTLA4) is a main negative regulator of the immune system, which inhibits the costimulatory signaling for T cells. Preclinical studies demonstrated that antibodies against CTLA4 induced regression of some murine tumors. Two CTLA4 blocking monoclonal antibodies have entered clinical development and are currently in pivotal clinical trial testing. Ipilimumab (formerly MDX010) is an IgG1 and tremelimumab (formerly CP-675,206 and transiently ticilimumab), is an IgG2, both being fully human monoclonal antibodies. Across several early clinical trials, including dose escalation, single dose, multi-dose, and in combination with a variety of other immune stimulants like peptide vaccines or interleukin-2, objective tumor responses in patients with metastatic melanoma have been observed in the in the range of 5 to 20%. A key feature is that some of these responses are extremely long-lived responses, lasting years. The early clinical testing also demonstrated that these CTLA4 blocking antibodies can lead to significant toxicities, most with an inflammatory or immune mediated mechanism of action. These include colitis and skin rash as the most common toxicities, and a variety of autoimmune and inflammatory processes against multiple organs. Some of these toxicities require immune suppressive therapy and may lead to permanent damage in occasional patients. In conclusion, two monoclonal antibodies blocking CTLA4 have demonstrated ability to break tolerance to self-tissues and result in long lasting objective cancer regressions, and have moved onto late stages of clinical development.
Insights
Blocking cytotoxic T lymphocyte-associated protein 4 (CTLA4) with monoclonal antibodies shows promise for cancer treatment, inducing long-lasting tumor regressions but also immune-related toxicities.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Cytotoxic T lymphocyte-associated protein 4 (CTLA4) negatively regulates T cell costimulatory signaling.
- Preclinical studies showed CTLA4 antibodies induced tumor regression in mice.
- Two fully human monoclonal antibodies, ipilimumab (IgG1) and tremelimumab (IgG2), target CTLA4.
Purpose of the Study:
- To evaluate the efficacy and safety of CTLA4 blocking antibodies in cancer patients.
- To assess the durability of treatment responses.
- To characterize the toxicities associated with CTLA4 blockade.
Main Methods:
- Clinical trials involving dose escalation, single/multi-dose regimens, and combination therapies.
- Administration of ipilimumab and tremelimumab to patients with metastatic melanoma.
- Monitoring for objective tumor responses and adverse events.
Main Results:
- Objective tumor responses observed in 5-20% of metastatic melanoma patients.
- Some responses were long-lived, lasting for years.
- Significant toxicities, primarily immune-mediated (e.g., colitis, rash), were noted.
Conclusions:
- CTLA4 blocking antibodies can overcome self-tissue tolerance, leading to durable cancer regressions.
- These antibodies have advanced to late-stage clinical development.
- Careful monitoring and management of immune-related toxicities are crucial.
