Modernizing Immunotherapy for Cutaneous T-cell Lymphoma

Written by

Steven Horwitz, MD, Memorial Sloan Kettering Cancer Center

Youn Kim, MD, Stanford Cancer Center

Alison Moskowitz, MD, Memorial Sloan Kettering Cancer Center

For decades, immunotherapy has been a cornerstone of systemic therapy for cutaneous T cell lymphoma (CTCL).

Commonly used therapies, such as interferon, retinoids, and extracorporal photopheresis (ECP), enhance anti-tumor immunity by activating some of the white blood cells that make up the body’s owns defenses against cancer.1 It is therefore not surprising that modern immune-therapies, which target anti-tumor immunity in more sophisticated ways, have the potential to greatly improve our treatments for CTCL. 

Pembrolizumab

Inhibition of the programmed death-1 (PD-1) pathway, often called immune checkpoint inhibition, is one of the most successful strategies for inducing anti-tumor immunity in many types of cancer. However, until recently there was very little data for its use in CTCL. In types of CTCL, like mycosis fungoides (MF) and Sezary Syndrome (SS), molecules (ligands) that attach to PD-1, called PD-L1, are widely present on either cancer cells or normal white blood cells that are around the cancer cells. This suggests that the PD-1 pathway is one way the cancer cells hide from or block the body’s immune system.2

A phase II study led by the Cancer Immunotherapy Trials Network (CITN) evaluating pembrolizumab, an antibody to PD-1, showed promising results in people with higher stages of or relapsed MF and SS.3 In this study, 24 people were treated and 38% had at least 50% improvement in their lymphoma. Furthermore, many of these people experienced long term and ongoing benefit from treatment. Based upon these results, pembrolizumab is now listed in national guidelines as a treatment option for CTCL treatment and future studies combining pembrolizumab with other immune therapies are planned. 

Brentuximab Vedotin

Another drug that was recently added to our armamentarium for CTCL is brentuximab vedotin (BV). BV is a drug with 2 parts – an antibody and chemotherapy, which are bound together. The antibody is designed to bind to a protein called CD30, which is often found on the surface of CTCL cells. When BV binds to CD30-positive tumor cells, it enters and kills the cells through the action of the chemotherapy.4

BV was recently evaluated in people with MF in a phase III study in which it was compared to methotrexate or bexarotene. BV was much more effective in treating MF than either of the other drugs (response rate to BV was 65% compared to 10% for the other drugs). BV can cause side effects; most common of which is neuropathy, or numbness in fingers and toes, however it is typically well tolerated. Based upon its impressive activity in MF, BV is listed in national guidelines as a treatment option for CD30 positive MF. 

Mogamulizumab

A drug that is not yet FDA approved (but may become approved for MF and SS) is mogamulizumab, an antibody that binds to a protein called CCR4. CCR4 is present on both tumor cells and immune cells. As a result, mogamuliziumab likely works by 2 mechanisms - it directly depletes tumor cells and enhances anti-tumor immunity.

This drug was evaluated in 41 people with MF or SS and 37% experienced at least 50% reduction in their lymphoma.5 It was next evaluated in a randomized study (phase III) in which it was compared to vorinostat. The results from this phase III study are not yet available. However, if the study shows that mogamulizumab is more active than vorinostat for MF or SS, it could lead to its FDA approval for these diseases. 
 

Additional immune therapies show promise

Additional immune therapies that show promising activity in MF and SS are currently being evaluated in clinical trials. One such drug is an antibody that binds to KIR3DL2, a protein present on CTCL tumor cells.6 Another interesting therapy is low dose skin radiation combined with an immune enhancer called IL-12.7 Both of these therapies are in early phases of study but have the potential to improve and broaden treatment options for CTCL. 

Overall, immune therapy continues to play an important role in the treatment of CTCL.

Newer immune therapies, such as pembrolizumab and BV, are already available and additional therapies may be close to approval. Given the past success of more traditional immune-modulatory therapies in CTCL, these modern approaches are likely to significantly improve treatment options for people with MF and SS.

 

References

1.    Kim EJ, Hess S, Richardson SK, Newton S, Showe LC, Benoit BM, Ubriani R, Vittorio CC, Junkins-Hopkins JM, Wysocka M, Rook AH. Immunopathogenesis and therapy of cutaneous T cell lymphoma. The Journal of clinical investigation 2005;115:798-812.

2.    Wilcox RA, Feldman AL, Wada DA, Yang ZZ, Comfere NI, Dong H, Kwon ED, Novak AJ, Markovic SN, Pittelkow MR, Witzig TE, Ansell SM. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood 2009;114:2149-58.

3.    Khodadoust M, Rook AH, Porcu P, Foss FM, Moskowitz AJ, Shustov AR, Shanbhag S, Sokol L, Shine R, Fling SP, Li S, Rabhar Z, Kim J, Yang Y, Yearley J, Chartash EK, Townson SM, Subrahmanyam PB, Maecker H, Alizadeh AA, Dai J, Horwitz SM, Sharon E, Kohrt H, Cheever MA, Kim Y. Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Clinical Efficacy in a Citn Multicenter Phase 2 Study. 2016.

4.    Kim YH, Whittaker S, Horwitz SM, Duvic M, Dummer R, Scarisbrick JJ, Quaglino P, Zinzani PL, Wolter P, Wang Y, Palanca-Wessels MC, Zagadailov E, Trepicchio WL, Liu Y, Little M, Prince HM. Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study. ASH Annual Meeting Abstracts 2016:Abstract 182.

5.    Duvic M, Pinter-Brown LC, Foss FM, Sokol L, Jorgensen JL, Challagundla P, Dwyer KM, Zhang X, Kurman MR, Ballerini R, Liu L, Kim YH. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. 2015.

6.    Bagot M, Porcu P, Ram-Wolff C, Khodadoust M, Battistella M, Marie-Cardine A, Mathieu S, Vermeer MH, Whittaker S, Duvic M, Bensussan A, Paturel C, Bonnafous C, Thonnart N, Widemann A, Bonin C, Sicard H, Paiva C, Pilz K, Kim Y. First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results. 2016.

7.    Duvic M, Sherman ML, Wood GS, Kuzel TM, Olsen E, Foss F, Laliberte RJ, Ryan JL, Zonno K, Rook AH. A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides. Journal of the American Academy of Dermatology 2006;55:807-13.