Moderna Inc (MRNA)

[jondoeuk]

You should know that CD163 only accounts for small population and they cannot suppress massive number of t-cells.

Based on the literature CD163hi macrophages are able to suppress T-cells.

In this paper, two HLA-matched patients with metastatic pancreatic ductal adenocarcinoma were treated with a TCR-T cell therapy (the TCRs came from a patient who responded to TIL therapy) [1].

In one patient, who had lung mets only, experienced a durable partial response after receiving 16.2 billion TCR-T cells. Looking into why therapy was more successful, one reason was due to the phenotype of the T-cells (CD45RO+CD103+CD69+CD49a+, so memory and tissue-resident).

However, after about a year, she showed slow progression. Dr. Tran has gone on to give more info at different medical/scientific conferences. She got a second infusion of TCR-T cells (that were more potent) plus an anti-PD-1. Looking at efficacy, at three months she had stable disease (~25% reduction by RECIST) and a six month scan showed stable disease as well. There were regressions of some lesions, but when comparing the scans (three months vs. six months) there was some growth in other lesions. At time they were thinking about the next steps.

Looking at two progressing lesions, the first genetically expressed the HLA and targeted antigen. It contained transduced T-cells as well, with the cells preferentially expressing TIM3, TIGIT, CD25 and IL7RA, suggestive of antigen encounter. It also displayed a high infiltration of non-transduced T-cells and CD163hi macrophages, often intimately co-localised with each other, both with the transduced and non-transduced T-cells.

As for the second progressing lesion (smaller), it contained a neutrophil infiltrate as well as CD163hi macrophages. Based on this, they are trying to further characterise what (neo)antigens might be recognised by the non-transduced T-cells in one of the progressing lesions. In addition, undertaking single-cell transcriptomics of infusion products and peripheral blood samples, and deeper molecular studies on tumour sections.

Merck makes the collaboration with Moderna look so real just like Merck signed the deal with Daiichi on three ADCs.

The first deal was in 2016. Under the terms of the agreement, MRK made an upfront cash payment to MRNA of $200 million. That was expanded in 2017 and amended in 2018, before MRK exercised its option to jointly develop and commercialise MRNA's vaccine in 2022. For the latter, MRK paid MRNA $250 million upfront. Now additional trials are planned.

Targeting for several neoantigens may have efficacy for a certain percentage of hot tumors.

MRNA's vaccine encodes up to 34 patient-specific neoantigens.

But it lacks of efficacy in treating cold tumors.

Autogene cevumeran (which encodes up to 20 patient-specific neoantigens), jointly developed by BNTX and RHHBY's Genentech, continues to show poly-specific T-cell responses and delayed tumour recurrence in patients with resected pancreatic ductal adenocarcinoma [2].

Based on the data, a randomised PhII trial is ongoing. Other randomised PhII trials, including in adjuvant CRC are ongoing as well.

If I am not mistaken, the trials between Merck and Moderna only target hot tumor.

So far, but MRNA's CEO has talked about testing the vaccine in ''cold'' tumours, including resected pancreatic ductal adenocarcinoma.

Refs:
1 https://www.nejm.org/doi/full/10.1056/NEJMoa2119662
2 https://www.nature.com/articles/s41586-024-08508-4