Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome.

“From http://www.sciencedirect.com - August 8, 6:16 AM
Abstract Monoallelic germline mutations in one of the DNA mismatch repair (MMR) genes cause Lynch syndrome, with a high lifetime risks of colorectal and endometrial cancer at adult age. Less well known, is the constitutional mismatch repair deficiency (CMMRD) syndrome caused by biallelic germline mutations in MMR genes. This syndrome is characterized by the development of childhood cancer. Patients with CMMRD are at extremely high risk of developing multiple cancers including hematological, brain and intestinal tumors. Mutations in MMR genes impair DNA repair and therefore most tumors of patients with CMMRD are hypermutated. These mutations lead to changes in the translational reading frame, which consequently result in neoantigen formation. Neoantigens are recognized as foreign by the immune system and can induce specific immune responses. The growing evidence on the clinical efficacy of immunotherapies, such as immune checkpoint inhibitors, offers the prospect for treatment of patients with CMMRD. Combining neoantigen-based vaccination strategies and immune checkpoint inhibitors could be an effective way to conquer CMMRD-related tumors. Neoantigen-based vaccines might also be a preventive treatment option in healthy biallelic MMR mutation carriers. Future studies need to reveal the safety and efficacy of immunotherapies for patients with CMMRD. Keywords Constitutional mismatch repair deficiency syndromeCMMRDNeoantigensCancer immunotherapyPrevention“


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Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome.

https://www.ncbi.nlm.nih.gov/pubmed/28645564/

“Abstract
Monoallelic germline mutations in one of the DNA mismatch repair (MMR) genes cause Lynch syndrome, with a high lifetime risks of colorectal and endometrial cancer at adult age. Less well known, is the constitutional mismatch repair deficiency (CMMRD) syndrome caused by biallelic germline mutations in MMR genes. This syndrome is characterized by the development of childhood cancer. Patients with CMMRD are at extremely high risk of developing multiple cancers including hematological, brain and intestinal tumors. Mutations in MMR genes impair DNA repair and therefore most tumors of patients with CMMRD are hypermutated. These mutations lead to changes in the translational reading frame, which consequently result in neoantigen formation. Neoantigens are recognized as foreign by the immune system and can induce specific immune responses. The growing evidence on the clinical efficacy of immunotherapies, such as immune checkpoint inhibitors, offers the prospect for treatment of patients with CMMRD. Combining neoantigen-based vaccination strategies and immune checkpoint inhibitors could be an effective way to conquer CMMRD-related tumors. Neoantigen-based vaccines might also be a preventive treatment option in healthy biallelic MMR mutation carriers. Future studies need to reveal the safety and efficacy of immunotherapies for patients with CMMRD.“

Biallelic mutations in MMR genes and their risk of cancerclick to collapse contents
Individuals with CMMRD are at increased risk for developing malignant gliomas, hematologic malignancies, and gastrointestinal tract cancers at young age. It is a highly penetrating cancer predisposition syndrome, with most biallelic mutation carriers developing cancer in the first two decades of life [8,9]. Hematological malignancies usually arise in infancy or early childhood and are more frequent in patients with MLH1 or MSH2 mutations than in patients with mutations in MSH6 or PSM2 [6]. The latter group appears to have a higher prevalence of brain tumors which develop later during childhood. CRC in patients with CMMRD is most frequently found as a second or third primary malignancy and arises in adolescence or young adulthood. The prevalence of CRC is higher in patients with biallelic PMS2 and MSH6 [6,22–24].

The treatment of childhood cancer is dependent of the specific location and the type of cancer. Since CMMRD is very rare, there is limited information on optimal therapeutic strategies. All described responses to chemotherapy are based on case report studies only. Chemotherapy treatment comes at the cost of toxicity. Therefore, careful selection of therapies is required for children with CMMRD. This should be based on the toxicity profile of specific agents as well as known tumor resistance to specific therapies [33].

MMR deficient cells are profoundly resistant to alkylating antineoplastic agents, such as temozolomide, cisplatin or busulfan. Temozolomide is frequently used in the standard treatment of glioblastomas multiforme (GBM) [10,34]. This is of clinical importance in patients with CMMRD, since it has become clear that these agents are less effective in MMR-deficient tumors and even may provide a growth advantage for the tumor cells [35]. Indeed, several studies have reported that treatment of GBM with temozolomide can promote further MMR deficiency due to loss of MSH2 or MSH6 expression, leading to temozolomide resistance [36,37]. In vitro studies also showed reduced sensitivity to the DNA damaging agents cisplatin and busulfan. Only one out of six patients with CMMRD-related GBM treated with temozolomide and radiotherapy showed a clinical response. The other patients' tumors were resistant to this therapy [10]. Another study showed that temozolomide treatment leads to accumulation of somatic mutations [38]. Moreover, temozolomide increases the risk of second primary tumors in patients with CMMRD because of their inability to repair the accumulated somatic mutations [9,10,39,40]. On the contrary, recent data supports that temozolomide treatment in glioma cells can boost the adaptive immune response [41].

Whether temozolomide, cisplatin and busulfan are safe in patients with CMMRD is still controversial and requires further clinical studies [10]. Until now it remains unclear which chemotherapeutic regimen is most effective and the least dangerous.

Advances in the development of personalized neoantigen-based therapeutic cancer vaccines


https://www.nature.com/articles/s41571-020-00460-2