Rich Immunotherapy Pipeline for Melanoma Under Way

Antagonistic Antibodies

The success of ipilumumab,¹as well as that of anti-programmed death 1 (PD-1) checkpoint inhibitors pembrolizumab²and nivolumab,³both now approved for metastatic melanoma, has demonstrated the potential for the use of antagonistic antibodies as immunotherapy.

Omid Hamid, MD, director, melanoma program, and chief, translational research and immuno-oncology at the Los Angeles Clinic and Research Institute in California, recently spoke about melanoma immunotherapies in the pipeline at the 11th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®.

“While the targeted agents may have higher response rates, we have not seen responses as durable as those seen with immunotherapy,”⁵Hamid said. “We have just begun to touch on the promise of immunotherapy. The future will elucidate optimal combinations of checkpoint inhibition and other immune-oncologic modalities and targeted agents.”

Table 1. Clinical Research of Cytokines in Melanoma

Phase

ClinicalTrials.gov Identifier

Cytokine

Expected Completion Date

I/II

NCT01397708

IL-12

September 2014

I

NCT01727076

IL-15

June 2015

II

NCT01363206

GM-CSF with ipilimumab

May 2015

Another anti PD-1 antibody in development for melanoma, pidilizumab (CT-011), recently reported its phase II results⁴(NCT01435369) and an antibody to programmed death ligand 1 (PD-L1), MSB0010718 (NCT01772004), is in an ongoing trial for solid tumors, including melanoma, and due to report in October 2016. These developments have opened the door to combination therapies. A phase III trial of nivolumab or nivolumab plus ipilimumab versus ipilimumab alone in patients with previously untreated advanced melanoma is scheduled for completion in November 2017 (NCT01844505).

Agonistic antibodies

Yet more targets for antagonistic antibodies are being researched. Preclinical research has suggested that T-cell immunoglobulin and mucin protein 3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and PD-1 define the autologous tumor reactive repertoire⁶and that anti-TIM-3 or anti-LAG-3 agents, when combined with anti PD-1 agents, lead to increased efficacy. It is expected that these agents will move into clinical trials.⁷Another possible antagonistic antibody in a phase I trial (NCT01918930) is MGA 271, which targets the receptor B7-H3, present on antigen presenting cells.⁸The study aims to gain a better understanding of the mechanism of action of the drug in patients with melanoma, and will be completed in February 2016. The drug will not be administered to patients, but used in pharmacodynamic studies on tumor biopsies.Agonistic antibodies may also hold promise in the immunotherapy arena. Varlimumab (CDX 1127) targets the CD27 costimulatory receptor on T cells, promoting their survival and activation. CD27 activation also influences the proliferation and cytotoxic activity of natural killer cells.^9-11Varlimumab is in a phase I safety trial in solid tumors, including metastatic melanoma (NCT01460134), and in a phase I/II trial (NCT02335918) in combination with nivolumab in solid tumors, including melanoma and metastatic melanoma of the head and neck.

Cytokines

The monoclonal agonistic antibody TRX528 activates the glucocorticoid-induced tumor necrosis factor receptor (GITR).¹²The downstream consequences of this include increases in the proliferation of T effector cells and attenuation of the suppressive effects of T regulatory cells. TRX528 was evaluated in a phase I trial for patients with stage III or IV malignant melanoma (NCT01239134). The trial completion date was December 2014, and the results are pending.The established efficacy of cytokines in melanoma has paved the way for clinical research on other cytokines, such as interleukin 12 (IL-12), IL-21, and IL-15 (for examples of ongoing/completed cytokine trials in melanoma seeTable 1). A trial of IL-21 in melanoma was completed in June 2014 and results are awaited (NCT01489059).

Adoptive T-Cell Therapy (ACT)

Table 2. Current Phase II Trials of ACT in Melanoma

Phase

ClinicalTrials.gov Identifier

Therapy

Expected Completion Date

II

NCT02062359

Anti-NY-ESO-1 TCR CD62L+ cells, aldesleukin, cyclophosphamide, fludarabine

June 2020

II

NCT01659151

ACT with TIL infusion, high-dose IL-2, vemurafenib, lymphodepletion

August 2016

II

NCT02027935

CD8+ T cells, IL-2, ipilimumab, cyclophosphamide

January 2019

TCR indicates T cell receptor

Vaccines

The impact of BRAF inhibition on the expression rates of melanoma differentiation antigens and other aspects of the immune response has led to an increased interest in this technique, and currently there are 16 phase I or II trials registered.⁸This approach is best prescribed in patients with slowly growing melanoma because of the time associated with the technique of preparing autologous tumor infiltrating lymphocytes.^8,13Table 2provides examples of current phase II trials of ACT in melanoma.Several types of cancer vaccines are in the pipeline undergoing clinical trials for melanoma, using:⁸

• Recombinant short peptides of tumor-associated antigen (TAA) or entire TAA proteins
• Cancer cell lysates
• Delivery of TAAs employing naked DNA, viral vectors. or RNA
• Autologous dendritic cells loaded with TAAs or engineered fusion proteins

Table 3. Vaccines in Most Advanced Stages of Clinical Development

Phase

ClinicalTrials.gov Identifier

Vaccine, Therapy Details

Expected Completion Date

III

NCT00477906

M-Vax, autologous, hapten-modified melanoma vaccine, BCG, cyclophosphamide, IL-2

January 2015

I/II

NCT01455259

AdCD40L therapy. Adenoviral serotype 5 vector, E1/E3 deleted. Human CD40L gene insert driven by RSV promotor.

December 2017

III

NCT01875653

Autologous dendritic cells and irradiated autologous tumor cells in GM-CSF

June 2022

BCG indicates Bacille Calmette-Guerin; RSV, respiratory syncytial virus.

Oncolytic Immunotherapy

Table 3gives examples of vaccines in the most advanced stages of clinical development for melanoma.Oncolytic immunotherapy is a major focus of clinical interest and research. The most clinically advanced is talimogene laherparepvec (T-VEC).

“T-VEC uses an attenuated herpes virus that can only replicate in malignant cells. Unfettered viral replication leads to focal cancer cell lysis while secreting GM-CSF, more virus capable of infecting other malignant cells, and tumor antigens creating an immune stimulatory environment,” said Hamid,⁵adding, “Today, T-VEC therapy has shown local and distant tumor response, improved response rates and tumor control, and a trend toward improved survival.”

The Pipeline and Future Prospects

The US Food and Drug Administration has scheduled an advisory hearing on April 29, 2015, to discuss a biologics license application for T-VEC,¹⁴which is undergoing phase I/II studies in melanoma, in combination with or without pembrolizumab (NCT02263508), completion date February 2019, and ipilimumab (NCT01740297), completion date November 2017.“Oncologists today have the mandate to reconfigure their preconceived notions of immunotherapy. The toolbox has expanded,” said Hamid, pointing out that “the need to familiarize oneself with these options is tantamount.”

Reflecting on the expected outcome of further approvals for specific immune therapies, and combination therapies adding considerably to treatment choices, Hamid concluded, “With the multitude of targeted therapies, immune modulators, and checkpoint inhibitors/agonists, extensive options exist.”⁵

References

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3. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf. Accessed March 12, 2015.
4. Atkins MB, Kudchadkar RR, Sznol M. Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma.J Clin Oncol. 2014;32:5s(suppl); Abstract 9001.
5. http://www.gotoper.com/publications/ajho/2015/2015Feb/New-Years-Resolution-Work-to-Do. Accessed March 13, 2015.
6. Gros A, Robbins PF, Yao X, Li YF, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors.J Clin Invest. 2014;124:2246-2259.
7. http://www.tesarobio.com/documents/2014AACRposterLB266.pdf. Accessed March 14, 2015.
8. Rotte A, Bhandaru M, Zhou Y, McElwee KJ. Immunotherapy of melanoma: Present options and future promises [published online ahead of print January 15, 2015].Cancer Metastasis Rev.
9. Thomas LJ, He LZ, Marsh H, Keler T. Targeting human CD27 with an agonist antibody stimulates T-cell activation and antitumor immunity.Oncoimmunology. 2014;3:e27255.
10. Denoeud J, Moser M. Role of CD27/CD70 pathway of activation in immunity and tolerance.J Leukoc Biol. 2011;89:195-203.
11. Schaer DA, Hirschhorn-Cymerman D, Wolchok JD. Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy.J Immunother Cancer. 2014;2:7.
12. http://gitrrx.com/therapeutic-program.php. Accessed March 13, 2015.
13. Weber J, Atkins M, Hwu P, et al. Immunotherapy Task Force of the NCI Investigational Drug Steering Committee. White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy.Clin Cancer Res. 2011;17:1664-1673.
14. http://www.onclive.com/web-exclusives/FDA-Schedules-Advisory-Meeting-for-T-VEC-in-Metastatic-Melanoma. Accessed March 14, 2015.

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