Page 24 - Haematologica Vol. 109 - July 2024

EDITORIAL
The clonal hydra: neoantigen-specific T-cell response in germ cell tumors
Shefali Mehra1 and Justin Taylor2
1Miller Medical School and 2Sylvester Comprehensive Cancer Center, Miami, FL, USA
Germ cell tumors (GCT) occur in men aged 15-35 years and are the most prevalent malignancies within this de- mographic. Over the past decade, introduction of plati- num-based therapeutics have proven to effectively treat GCT and improve outcomes.1 GCT, while predominantly occurring in the testes, can be found to originate in the mediastinum, accounting for 10% of all mediastinal neo- plasms.2 Mediastinal GCT pose a unique challenge to clinicians due to their propensity for the development of other malignancies. One in every 17 patients with a mediastinal GCT will develop a hematologic malignan- cy.3,4 Apart from hematologic malignancies, sarcomas and carcinomas can develop in patients with mediastinal GCT. Despite the success of platinum-based regimens in testicular GCT, primary mediastinal GCT have proven to be resistant to platinum-based agents, necessitating al- ternative treatment strategies.5 Interestingly, it has been shown that GCT and hematologic malignancies arising in the same individual share the presence of isochromosome 12p [i(12p)].6,7 Using whole exome sequencing, Taylor and colleagues definitively showed that these malignancies arise from a progenitor that can differentiate into GCT, sarcomas, or hematologic malignancies.8 Despite the improved understanding of their origin, the outcomes for mediastinal GCT with secondary somatic tumors is around 6 months, making discovery of novel treatments for these patients imperative.
Genoud et al. report results of a case study consisting of a 22-year-old male with a mediastinal PLAP-positive mixed GCT with CD61+ large cells.9 The patient’s bone marrow was infiltrated with CD34-, CD61+, and CD43+ cells with multilobulated nucleus and eosinophilic cytoplasm showing polyploidy, +der(3), and i(12p) on cytogenic anal- ysis. Following a diagnosis of synchronous acute myeloid leukemia (AML) and primary mixed GCT, the patient was initially treated with three cycles of cytarabine, mitoxan- trone, etoposide, and cisplatin. Intrathecal therapy con-
sisting of methotrexate, cytarabine, and methylprednisone was administered during the second cycle. Moreover, two additional cycles of etoposide and cisplatin were given. The patient achieved complete leukemic remission and metabolic activity of the mediastinal mass was shown to have decreased. Following conditioning, the patient underwent an allogeneic hematopoietic stem cell trans- plant (HSCT) from a mismatched unrelated donor with CD34+ harvested donor cells. Six months after HSCT, the patient was found to have 60% increased mass of residual and metabolic activity with biopsy showing a fusiform sarcoma with angiomatous differentiation. Ten months after HSCT, the patient was given two donor lympho- cyte infusions (5x105 and 6x106 CD3+ cells/kg). Ultimately, complete donor chimerism was obtained and persistent complete hematologic remission was achieved such that no neoplastic disease was found even 10 years after HSCT. Somatic mutations from the three tumors were used in order to identify mutation-specific neoantigens by filtering through the following criteria: major histocompatibility complex binding affinity, strong binding affinity compared to normal proteins, and protein expression in cancer. Identification of 84 common neoepitopes that played a role in recognition of mutation-specific proteins revealed the sarcoma-specific neo-peptide IL36G16-24YPSMCKPIT, which elicited a positive response when tested in inter- feron-γ ELISPOT assays with the patient’s peripheral blood mononuclear cells. Furthermore, the neoantigen response to IL36G16-24YPSMCKPIT was, remarkably, detected in the patient’s peripheral blood mononuclear cells 7 years post- HSCT. Tumor exon sequencing revealed 48 somatic muta- tions detected in the GCT, 17 in the leukemia, and 331 in the sarcoma with phylogenic reconstruction revealing 13 shared events between the three malignancies confirming a common clonal origin. A TP53 driver splice site mutation, chromosome 17 splice site mutation involving CDK12, and five loss of heterozygosity events including PTEN loss of
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Correspondence: J. Taylor Jxt1091@miami.edu
Received: Accepted: Early view:
January 9, 2024. January 15, 2024. January 25, 2024.
https://doi.org/10.3324/haematol.2023.284862
©2024 Ferrata Storti Foundation Published under a CC BY-NC license