Combination Therapy Paves the Way Forward for CTLA-4 Antibodies

Jane de Lartigue, PhD
Published: Monday, Feb 29, 2016

Five years after its debut, ipilimumab (Yervoy) has revolutionized the treatment of patients with metastatic melanoma and ushered in the era of immune checkpoint inhibitors into anticancer therapies.

Now, however, the CTLA-4 inhibitor has been eclipsed by anti-PD-1 antibodies, which are approved not only in melanoma but also in non–small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Although ipilimumab continues to demonstrate strikingly durable responses in melanoma, some lasting up to a decade, these occur in the minority of patients and a frustrating dearth of predictive biomarkers makes it hard to pick those patients out from the crowd.

Nevertheless, new research is carving out a role for ipilimumab and a second CTLA-4-targeting drug, tremelimumab, as combination therapy with potential in a variety of solid tumors. In addition to combinations with other immune checkpoint inhibitors, the agents are being evaluated across a breadth of other strategies, including in combination with conventional cytotoxic therapies, targeted therapies, and other types of immunotherapy (Table).

A Breakthrough for Immunotherapy

The identification of signaling pathways that control the activity of T cells, a central component of the immune response, has paved the way for checkpoint blockade agents.

Activation of T cells requires a dual signal. First, specific antigens are presented to the T cell and engage the T-cell receptor (TCR) on its surface. This is amplified by a second antigen-nonspecific costimulatory signal, resulting from the interaction between costimulatory molecules expressed on the T cell and antigen-presenting cell (APC). The best characterized costimulatory signal is generated by CD28 on the T cell, binding to B7-1 (CD80) or B7-2 (CD86) on the APC. Alternatively, T-cell activation can be inhibited at this second step, via the action of coinhibitory signals.

Stimulatory and Inhibitory Responses Mediated by Immune Checkpoints

Stimulatory and Inhibitory Responses Mediated by Immune Checkpoints

CTLA-4 is among many immune system regulators with cellular effects. Stimulatory effects are depicted with green arrows, and inhibitory effects are depicted with red symbols. PD-1, KIR, LAG-3, GITR, and TIM-3 are immune checkpoints.

DC indicates dendritic cell; MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell receptor; T REG, regulatory T cell.

Patel MA, Kim JE, Ruzevick J, Lim M. Present and future of immune checkpoint blockade: monotherapy to adjuvant approaches. World J Immunol. 2015;5(1):1-15. Reprinted with permission.

One of the best known coinhibitory signals is cytotoxic T-lymphocyte antigen (CTLA-4). This receptor is usually found in the cytoplasm but, upon activation of the TCR, is transported to and expressed on the cell surface. CTLA-4 has a higher binding affinity than CD28 for CD80 and CD86 and it outcompetes the costimulatory signal.

Ipilimumab and Tremelimumab Emerge

Once it became clear that CTLA-4 functioned as a T cell off-switch, it was thought that blocking its activity might help to reinstate antitumor immunity. In 2011, research into the strategy culminated in the FDA's approval of ipilimumab for the treatment of metastatic melanoma. It was the first treatment in more than 30 years to provide a significant survival benefit for patients with this cancer type. The pivotal clinical trials included a phase III, randomized trial in previously treated patients with unresectable or metastatic melanoma in which a combination of ipilimumab and the glycoprotein 100 (gp100) peptide vaccine was compared with ipilimumab monotherapy or gp100 monotherapy. Both ipilimumab-containing arms demonstrated an overall survival (OS) benefit compared with the vaccine alone (median OS was 10 months, 10.1 months, and 6.4 months, respectively).

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