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Intratumorally Anchored Cytokine Therapy

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Summary written by Czeslaw Radziejewski, Ph.D.

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including K. Dane Wittrup, Professor of Chemical Engineering and Biological Engineering, Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, who discussed “Intratumorally Anchored Cytokine Therapy”.

As a result of advances in interventional radiologic, endoscopic, and laparoscopic procedures, most cancer tissues can now be accessed for a local injection directly into the tumor, with the aim of triggering an immune response that will act globally against cancer. Because of their anti-tumor activity and synergistic behavior, cytokines such as IL-2, IL-12, and interferons are currently considered for intratumoral therapies. Cytokine exposure is spatiotemporally programmed during immune responses, which means cytokines are present at certain places at certain times and in a particular order. As therapeutic agents, optimally they should be supplied in particular tissues at particular times for a specific duration. Direct cytokine injection into tumors has been attempted, but this approach was previously unsuccessful because of leakages out of the target tissue and systemic toxicity.

In his presentation, Prof. Wittrup described two strategies to localize cytokines to the target tissue that could allow for efficacious levels to be reached without overall toxicity. Both methods take advantage of retaining cytokines at the site of injection through interaction with collagen. [1,2,3] One approach relies on anchoring cytokines to the collagen-binding extracellular protein Lumican and the other relies on anchoring cytokines to the vaccine adjuvant Alum (aluminum hydroxide). Alum forms clusters of nanocrystals that are positively charged, which, when injected, tend to stay at the injection site. Because phosphorylated proteins bind very strongly to Alum, cytokines are fused to a proprietary peptide called alum peptide. The construct is co-expressed with kinase Fam20C, which attaches multiple phosphates to the peptide. Phosphorylated cytokine is then mixed with Alum and injected into the tumor site. Lumican binds to collagen type 1 and type 4, and Alum binds to collagen type 1. Lumican anchored molecules stay in place for 2 to 3 days. Alum anchoring increases tumor exposure to more than three weeks.

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FDA approves anti-LAG-3 relatlimab-rmbw as part of a combination therapy for melanoma

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On March 18, 2022, Bristol Myers Squibb announced that Opdualag a fixed-dose combination of anti-PD-1 nivolumab and relatlimab-rmbw, administered as a single intravenous infusion, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

Relatlimab (BMS-986016, ONO4482) is a human IgG4k antibody that targets LAG-3, which, like PD-1, is an immune checkpoint. Bristol Myers Squibb and Ono have a strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea, and Taiwan. An marketing authorization application is undergoing evaluation by the European Medicines Agency.

FDA’s approval was based on data from the Phase 2/3 RELATIVITY-047 trial (NCT03470922), which evaluated the effects of relatlimab combined with nivolumab versus nivolumab in a total of 714 patients with previously untreated metastatic or unresectable melanoma. Patients were randomized 1:1 and administered a fixed-dose combination of 160 mg relatlimab and 480 mg nivolumab or 480 mg nivolumab by intravenous infusion every 4 weeks until disease recurrence, unacceptable toxicity or withdrawal of consent. The study’s primary endpoint, progression-free survival (PFS) by blinded independent central review, was met. The median PFS in the group that received both relatlimab and nivolumab (n=355) was significantly longer (10.1 months [95% CI, 6.4–15.7]) than in the group that received nivolumab only (4.6 months [95% CI, 3.4–5.6]; hazard ratio: 0.75 [95% CI, 0.6–0.9]; P = 0.0055). [1]

1. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386:24-34.

Opdualag is the 4th antibody-based therapeutic granted a first approval for marketing in the EU or US in 2022. Explore our searchable table of antibody therapeutics approved in the EU or US for details.

FDA approves KIMMTRAK® (tebentafusp-tebn) for unresectable or metastatic uveal melanoma

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On January 26, 2022, Immunocore Holdings plc announced the approval from the United States Food and Drug Administration (FDA) of KIMMTRAK® (tebentafusp-tebn) for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM). Tebentafusp (IMCgp100) is a bispecific fusion protein composed of: 1) a T cell receptor (TCR) recognizing a human leukocyte antigen (HLA)-A*02:01 complexed with a peptide derived from gp100 antigen expressed by melanoma cells, and 2) an antibody single-chain variable fragment that binds CD3 present on T cells. Developed by Immunocore, this molecule creates a bridge between tumor cells and immune cells, and thus facilitates tumor-cell killing by T cells. As the TCR domain recognizes a peptide presented on HLA-A*02:01, tebentafusp can only be used to treated patients expressing this HLA type. Tebentafusp has been granted Breakthrough Therapy, Fast Track, and Orphan Drug designations by the FDA.

The marketing applications are based on a late-stage clinical trial (NCT03070392) that enrolled 378 patients with advanced uveal melanoma who were HLA-A*0201–positive. In the study, patients were randomized 2:1 to receive tebentafusp or investigator’s choice of therapy (either pembrolizumab, ipilimumab, or dacarbazine). Tebentafusp was administered at a dose of 20 micrograms on cycle 1 Day 1, then 30 micrograms on cycle 1 Day 8, then 68 micrograms on cycle 1 Day 15 and weekly thereafter by IV infusion over 15 minutes until confirmed disease progression or unacceptable toxicity. The primary outcome measure is overall survival. As reported in September 2021, the OS Hazard Ratio in the intent-to-treat population favored KIMMTRAK, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine). Moreover, the 1-year survival rate was 73% for patients in the experimental arm vs. 59% in the investigator’s choice arm.

The European Medicines Agency, the United Kingdom’s Medicines and Healthcare Regulatory Agency, Health Canada, and the Australian Government Department of Health Therapeutic Goods Administration have accepted the submission of Marketing Authorisation Applications for tebentafusp.

KIMMTRAK is the 1st antibody-based therapeutic granted a first approval for marketing in the EU or US in 2022. Explore our searchable table of antibody therapeutics approved in the EU or US for details.

Antibody therapeutics for melanoma

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May is Melanoma Awareness Month, with awareness campaigns kicking off on the first Monday (May 3rd in 2021). Melanoma is caused by cancerous melanocytes, which are cells in the epidermis that normally make a pigment, melanin, that protects other skin cells from damaging sun rays. The American Cancer Society (ACS) estimates the lifetime risk for developing the disease is ~ 2.6% (1 in 38) for whites, and 0.6% (1 in 167) for Hispanics, and 0.1% (1 in 1,000) for Blacks. Overall, melanoma is more common in men, and the risk of melanoma increases with age. The ACS’ data suggest that ~ 106,110 new melanomas will be diagnosed (~62,260 in men and 43,850 in women) and ~ 7,180 people may die of the disease in the United States during 2021.

Approved antibody therapies for melanoma

Three antibody therapeutics (ipilimumab, nivolumab, pembrolizumab)  that target the immune checkpoints CTLA-4 (CD152) or programmed cell death protein 1 (PD-1, CD279) are approved for melanoma.

  • YERVOY (ipilimumab), which targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is indicated for the treatment of unresectable metastatic melanoma in adults and pediatric patients (12 years and older) and adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.
  • KEYTRUDA (pembrolizumab), which targets PD-1, is indicated for the treatment of patients with unresectable or metastatic melanoma, and for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.
  • OPDIVO (nivolumab), which targets PD-1, is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression, including following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, and for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Combination therapy was shown to be superior to monotherapy with these checkpoint inhibitors in the Phase 3 Checkpoint study, which evaluated nivolumab monotherapy or nivolumab combined with ipilimumab versus ipilimumab monotherapy in patients with previously untreated unresectable or metastatic melanoma. The overall survival (OS) at 5 years was 52%, 44% and 26% in the nivolumab-plus-ipilimumab, nivolumab monotherapy, and ipilimumab monotherapy groups, respectively. However, Grade 3 or 4 treatment-related adverse events occurred more frequently in patients who received combination therapy (59%, 23%, and 28% of patients in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab treatment groups, respectively).

Investigational antibody therapies for melanoma

While the antibody therapeutics that target CTLA-4 and PD-1 have benefited melanoma patients, biopharmaceutical companies are developing novel antibody therapeutics that target other immune checkpoints such as LAG-3 or use different mechanisms of action.

  • Bristol-Myers Squibb is developing relatlimab (BMS-986016), which is a human IgG4 antibody targeting LAG-3 on T cells, thereby restoring effector function of exhausted T cells. Primary results from the Phase 2/3 RELATIVITY-047 (CA224-047) trial evaluating the fixed-dose combination of relatlimab and Opdivo (nivolumab) versus Opdivo alone in patients with previously untreated metastatic or unresectable melanoma indicated that the trial met its primary endpoint of progression-free survival.
  • Philogen  S.p.A. is developing Nidlegy, which is composed of two single-chain variable fragment (scFv)-based immunocytokines that target extra-domain B of fibronectin (L19IL2 + L19TNF combination), as neoadjuvant intralesional treatment for melanoma patients with locoregional disease. Two randomized, controlled Phase 3 registration trials for intralesional application of Nidlegy as a neoadjuvant followed by surgery + eventual adjuvant treatments (standard of care) and compared to standard of care are currently ongoing in Europe (PIVOTAL; NCT02938299) and in the USA (Neo-DREAM; NCT03567889) in patients with fully resectable stage IIIB/C melanoma.
  • Immunocore Ltd is developing tebentafusp, which comprises a high- affinity T cell receptor specific to a peptide sequence from the gp100 antigen, which is presented on melanoma tumor cells by HLA-A2, fused to an anti-CD3 single chain antibody fragment. In a Phase 3 study, tebentafusp demonstrated a statistically significant and clinically meaningful improvement in OS as a first-line treatment in metastatic uveal melanoma.  Tebentafusp has been granted Breakthrough Therapy Designation, Fast Track designation and orphan drug designation by the FDA and Promising Innovative Medicine designation under the UK Early Access to Medicines Scheme for metastatic uveal melanoma. Immunocore will be working with the FDA to complete submission of a BLA for tebentafusp in the third quarter of 2021.

The Antibody Society continuously collects data for antibody therapeutics in the commercial clinical pipeline. We will provide updates on the antibody therapeutics being evaluated for melanoma in future posts.

Need help keeping up to date on US and EU approvals?

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.