Tumor Immunotherapies Combine Big for Synergy in Phase I Trials

Two immune-cell-targeting immunotherapies have already won FDA approval for treating cancer. The first was Provenge (Sipuleucel-T), an autologous dendritic cell vaccine from Dendreon Corporation. It was approved in 2010 for hormone-refractory metastatic prostate cancer. The second was Ipilimumab, an antibody that blocks CTLA-4, a major negative regulator of T cell activation. It was approved in 2011 for late-stage melanoma. Antagonists to PD-1 (such as Nivolumab) and PD-L1 — another receptor/ligand pair that suppresses T cells — are expected to join this group by 2015.

Early results from combination trials show something exciting: pairing several immunotherapies together can produce strong synergy. A report in the June edition of The New England Journal of Medicine by Wolchok et al. found deep, durable tumor regression when Ipilimumab and Nivolumab were combined in patients with advanced metastatic melanoma.

How CTLA-4 and PD-1 Suppress T Cell Activity

CTLA-4 and PD-1 are checkpoint receptors found on activated T cells. Both share structural similarity with CD28, a co-stimulatory receptor on T cells.

• CTLA-4 competes with CD28 for binding to CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells. This blocks CD28 activation signals and pulls inhibitory molecules into the T cell receptor (TCR) signaling complex.
• PD-1 binds ligands from the same B7 family — PD-L1 (B7H1) and PD-L2 (B7-DC). These ligands are upregulated on tumor cells, stromal cells, and activated antigen-presenting cells. When PD-1 binds them, it recruits the phosphatases SHP1 and SHP2, which shut down TCR signaling.

CTLA-4 and PD-1 work through separate, non-redundant pathways. This led researchers to predict that blocking both at once would produce a synergistic boost in T cell activity against cancer — a synergy already confirmed in mouse tumor models.

Building on Earlier Clinical Trial Results

Earlier trials had already tested these drugs on their own:

• Bristol-Myers Squibb’s Ipilimumab (MDX-010, Yervoy, IgG1), with or without a gp100 peptide vaccine, extended overall survival in previously treated metastatic melanoma patients by almost 4 months compared to the gp100 vaccine alone.
• In a separate study, adding Ipilimumab to dacarbazine (versus dacarbazine alone) in untreated metastatic melanoma patients extended survival by roughly two months, and improved survival rates at 1, 2, and 3 years.
• Bristol-Myers Squibb’s PD-1-blocking antibody (BMS-936558, IgG4) also showed strong clinical efficacy on its own in advanced non-small-cell lung cancer, melanoma, and renal-cell cancer.

Combining Ipilimumab and Nivolumab

In this dose-escalation phase I trial, Wolchok et al. treated 53 patients with advanced melanoma using Ipilimumab and Nivolumab concurrently, and 33 patients sequentially. A phase I trial is designed mainly to test safety, but the results in the concurrently treated group drew significant attention:

• 40% of patients had an objective response (by modified WHO criteria).
• 16 patients saw their tumor burden shrink by 80% or more at 12 weeks — 5 of these were complete responses.
• Responses came faster and were more pronounced than in earlier trials testing either drug alone.
• The reduction in tumor burden held up well over time in patients who responded.
• Responses occurred even in patients with PD-L1-negative tumors, despite PD-L1 tumor expression being proposed elsewhere as a predictor of Nivolumab’s efficacy.

Researchers are now awaiting phase III results comparing this combination against each drug alone.

The combination also came with more side effects than either drug alone had shown in previous trials. No treatment-related deaths occurred, but:

• 72% of patients had grade 3 or 4 adverse events.
• 53% had treatment-related grade 3 or 4 adverse events.
• 21% stopped therapy because of treatment-related adverse events.

Doctors managed these side effects with immunosuppressant or hormone-replacement therapies.

Many cancer immunotherapies are now in clinical trials, and several combine multiple modalities in hopes of this same kind of synergy. This trial shows that anti-tumor T cells are already present in tumor-bearing patients — when freed from inhibition, they can meaningfully help kill tumors. This is an exciting time for cancer immunology.

Further Reading:

Nivolumab plus Ipilimumab in Advanced Melanoma.  Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. N Engl J Med. 2013 Jun 2.

Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. Topalian, S.L. et al. N. Engl. J. Med. 366, 2443–2454 (2012).

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. Hodi, F.S. et al. N. Engl. J. Med. 363, 711–723 (2010).

Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.  Robert C, Thomas L, Bondarenko I, O’Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. N Engl J Med. 2011 Jun 30;364(26):2517-26.

Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma.  Lipson EJ, Drake CG. Clin Cancer Res. 2011 Nov 15;17(22):6958-62.