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TIL Therapy for Melanoma: Targeting MAAs & Neoantigens

1. What Are TILs?

Tumor-infiltrating lymphocytes (TILs) are immune cells that have migrated into the tumor microenvironment. In melanoma, they typically recognize two main classes of antigens:

  • Melanoma-Associated Antigens (MAAs) – shared tumor/self-antigens, often overexpressed in melanoma cells.
  • Neoantigens – patient-specific mutated peptides, unique to the tumor.


2. Melanoma-Associated Antigens (MAAs) Commonly Targeted by TILs

Cancer-Testis Antigens (CTAs):

Differentiation Antigens:

Drawing of cancer cells and a CD8+ T cell recognizing a cancer-specific antigen
Packaging of the peptides with a world map in the background

peptides & elephants provides validated peptides and peptide pools for several of these antigens (e.g., PRAME, NY-ESO-1, MAGE-A), ideally suited for T cell assays, epitope screening, and immunomonitoring.

Packaging of the peptides with a world map in the background

peptides & elephants provides validated peptides and peptide pools for several of these antigens (e.g., PRAME, NY-ESO-1, MAGE-A), ideally suited for T cell assays, epitope screening, and immunomonitoring.

3. TIL Reactivity to Neoantigens

Key features of neoantigens:

  • Exclusively expressed in tumor cells.
  • Arise from mutations → unique amino acid sequences.
  • Highly immunogenic due to lack of immune tolerance.

Clinical findings:

  • Neoantigen-specific TILs can expand hundreds-fold in vivo.
  • Responses often correlate with tumor regression and durable remissions.
  • Both CD8+ and CD4+ subsets contribute to tumor killing.

4. Strategies to Enrich Potent TIL Populations

  • NeoExpand – selective in vitro expansion of neoantigen-reactive TILs using IL-2 and APCs. [1]
  • NeoScreen – pre-exposure of tumor cells to selected neoantigens to broaden reactivity. [2]
  • Antigen-specific sorting – using MHC multimers for MAAs or neoantigen peptides.

5. Translational Outlook in Melanoma

  • MAA-focused approaches allow use of well-characterized, off-the-shelf peptides.
  • Neoantigen-based approaches deliver unmatched tumor specificity.
  • Combination strategies are under study to maximize TIL diversity and clinical benefit.
Drawing of a scientist pipetting at the bench

Pfeil-nach-rechts

 

For further reading see our blog post:
Neoantigene-Specific T-Cells in TIL Therapy

6. Summary Table

Antigen Class

Examples

Specificity

Clinical Notes

MAAs

PRAME, NY-ESO-1, MAGE-A family, SSX-2, SSX-4, MART-1, gp100, Tyrosinase, TRP-1, TRP-2

Tumor-associated; some
expression in healthy tissue

Broader patient coverage; available as validated peptides

Neoantigens

Patient-specific mutated peptides

Tumor-exclusive

Requires sequencing & prediction; highly immunogenic

Other Tumor Types – Other Antigens

While melanoma TILs predominantly target MAAs and Neoantigens, in virus-associated cancers (e.g., HPV-positive cervical cancer, EBV-driven nasopharyngeal carcinoma) TILs can also recognize viral antigens such as HPV E6/E7 or EBV latent proteins. These are not typically relevant for melanoma but are important in the broader TIL therapy landscape.

Working with patient-specific neoantigens?

peptides&elephants also offers custom peptide synthesis to support personalized T cell studies and therapeutic development.

drawing of the core element of the USPS platform controlled by a scientist

Literature

  1. Levin, Noam et al. “Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes.” Journal for immunotherapy of cancer vol. 12,5 e008645. 30 May. 2024, doi:10.1136/jitc-2023-008645
  2. Arnaud, M., Chiffelle, J., Genolet, R. et al. Sensitive identification of neoantigens and cognate TCRs in human solid tumors. Nat Biotechnol 40, 656–660 (2022). https://doi.org/10.1038/s41587-021-01072-6

Other Tumor Types – Other Antigens

While melanoma TILs predominantly target MAAs and Neoantigens, in virus-associated cancers (e.g., HPV-positive cervical cancer, EBV-driven nasopharyngeal carcinoma) TILs can also recognize viral antigens such as HPV E6/E7 or EBV latent proteins. These are not typically relevant for melanoma but are important in the broader TIL therapy landscape.

Working with patient-specific neoantigens?

peptides&elephants also offers custom peptide synthesis to support personalized T cell studies and therapeutic development.

drawing of the core element of the USPS platform controlled by a scientist

Literature

  1. Levin, Noam et al. “Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes.” Journal for immunotherapy of cancer vol. 12,5 e008645. 30 May. 2024, doi:10.1136/jitc-2023-008645
  2. Arnaud, M., Chiffelle, J., Genolet, R. et al. Sensitive identification of neoantigens and cognate TCRs in human solid tumors. Nat Biotechnol 40, 656–660 (2022). https://doi.org/10.1038/s41587-021-01072-6
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