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Clinical Trial
. 2018 Dec 19;18(1):1274.
doi: 10.1186/s12885-018-5193-9.

A phase II trial of recombinant MAGE-A3 protein with immunostimulant AS15 in combination with high-dose Interleukin-2 (HDIL2) induction therapy in metastatic melanoma

Jennifer L McQuade  1 , Jade Homsi  2 , Carlos A Torres-Cabala  3 , Roland Bassett  4 , Rashmi Murthy Popuri  5 , Marihella L James  5 , Luis M Vence  6 , Wen-Jen Hwu  5
Affiliations
Clinical Trial

A phase II trial of recombinant MAGE-A3 protein with immunostimulant AS15 in combination with high-dose Interleukin-2 (HDIL2) induction therapy in metastatic melanoma

Jennifer L McQuade et al. BMC Cancer. .

Abstract

Background: HDIL-2 is approved for advanced melanoma based on its durable antitumor activity. MAGE-A3 cancer immunotherapeutic (MAGE-A3 CI) is a recombinant MAGE-A3 protein combined with an immunostimulant adjuvant system and has shown antitumor activity in melanoma. We assessed the safety and anti-tumor activity of HDIL-2 combined with MAGE-A3 CI in advanced melanoma.

Methods: Patients with unresectable Stage III or Stage IV MAGE-A3-positive melanoma were enrolled in this phase II study. Treatment included an induction phase of MAGE-A3 CI plus HDIL-2 for 8 cycles followed by a maintenance phase of MAGE-A3 CI monotherapy. The primary endpoints were safety and objective response assessed per RECIST v1.1. Immune biomarker and correlative studies on tumor and peripheral blood were performed.

Results: Eighteen patients were enrolled. Seventeen patients were evaluable for safety and sixteen for response. Responses occurred in 4/16 (25%) patients with 3 complete responses, and stable disease in 6/16 (38%) patients with a disease control rate of 63%. The median duration of response was not reached at median follow-up of 36.8 months. Induction therapy of HDIL-2 + MAGE-A3 CI had similar toxicities to those reported with HDIL-2 alone. Maintenance MAGE-A3 monotherapy was well-tolerated. Increased immune checkpoint receptor expression by circulating T regulatory cells was associated with poor clinical outcomes; and responders tended to have increased tumor infiltrating T cells in the baseline tumor samples.

Conclusions: The safety profile of HDIL-2 + MAGE-A3 CI was similar to HDIL-2 monotherapy. Maintenance MAGE-A3 CI provides robust anti-tumor activity in patients who achieved disease control with induction therapy. Immune monitoring data suggest that MAGE-A3 CI plus checkpoint inhibitors could be a promising treatment for MAGE-A3-positive melanoma.

Trial registration: ClinicalTrials.gov, NCT01266603 . Registered 12/24/2010, https://clinicaltrials.gov/ct2/show/NCT01266603.

Keywords: HDIL-2; Immunotherapy; MAGE-A3 CI; Melanoma.

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Conflict of interest statement

Author’s information

Not applicable

Ethics approval and consent to participate

The study protocol and all amendments were approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center (protocol #2010–0113). The study was conducted in accordance with the protocol and its amendments, Good Clinical Practice Guidelines, and the Declaration of Helsinki. All patients provided written informed consent.

Consent for publication

N/A

Competing interests

W.-J. Hwu reports funding to the institution for clinical research from Bristol-Myers Squibb, MedImmune, and Merck & Co., Inc. and serving on an advisory board for Merck & Co., Inc.

Jade Homsi reports speaking and consulting with Merck & Co., Inc.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Clinical Response. a Waterfall plot indicating best RECIST 1.1 response as % change in lesion size from baseline. Red = complete response (CR). Yellow = partial response (PR). Orange = stable disease (SD). Green = progressive disease (PD). b Swimmer’s plot indicating duration of response. Red = complete response (CR). Yellow = partial response (PR). Orange = stable disease (SD). Green = progressive disease (PD). Vertical line = end of HDIL-2 + MAGE-A3 CI induction phase and beginning of maintenance phase. Blue triangle = time of partial response. Black triangle = time of complete response. Black circle = disease progression. Horizontal arrow = duration of response. X = death
Fig. 2
Fig. 2
Baseline immune infiltrates in responders and non-responders. Eleven patients had baseline specimens available for immunohistochemistry. a Percentage of positive CD8, CD45-RO, Granzyme B, and PD-1 TILs in tumor specimens corresponding to responders (R) and non-responders (NR) patients. b Representative images of tissue sections from responders (R) and non-responders (NR) patients showing subsets of TILs expressing CD8, CD-45RO, PD-1 (× 100) and Granzyme B (× 200) (immunohistochemistry)
Fig. 3
Fig. 3
Changes in immune checkpoint expression of peripheral blood regulatory T cells with therapy. Compared to responders, non-responders show a relative increase in the expression of multiple immune checkpoint molecules on regulatory T cells on treatment including [41BB (p = 0.04), CTLA4 (p = 0.01), and LAG3 (p = 0.02)]
Fig. 4
Fig. 4
MAGE-A3 positive peripheral CD8 cells and tumor response. a Peripheral blood flow cytometry of MAGE-A3+ CD8 T cells over time in 9 HLA-A2.1+ patients using an HLA-A2.1-restricted MAGE-A3 epitope. Patient 16 with complete response (red) shows high MAGE-A3 + CD8 cells at baseline and a robust increase in MAGE-A3 + CD8 cells early on treatment. Non-responding patients shown in black and patient with prolonged stable disease in yellow. b. Cross-sectional CT images of patient 16 who had lung metastasis at baseline, achieved a partial response at 18 months and a complete response at 32 months. White arrow indicates lung metastasis
See this image and copyright information in PMC

References

    1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723. doi: 10.1056/NEJMoa1003466. - DOI - PMC - PubMed
    1. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516. doi: 10.1056/NEJMoa1103782. - DOI - PMC - PubMed
    1. Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The Lancet Oncology. 2016;17:1248–1260. doi: 10.1016/S1470-2045(16)30122-X. - DOI - PubMed
    1. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–1888. doi: 10.1056/NEJMoa1406037. - DOI - PubMed
    1. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. doi: 10.1056/NEJMoa1504030. - DOI - PMC - PubMed

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