Replies to post #13961 on Moderna Inc (MRNA)

[jondoeuk]

Tumors don't have chance to adapt if DCs can present hundreds of tumor-associated antigens to immune system.

Cancer cells can mutate in real time to evade treatment as well [1,2]. In this, 17% innately have HLA LOH [3], but other papers put it (much) higher.

Also, many TAAs are self-antigens. As a result of negative selection, to prevent autoimmunity, any T-cell that is able to target a TAA will express a TCR with a low affinity. But TCRs with high affinity (for TAAs) are required for efficient antitumour immunity [4]. This is why ADAP (and other companies) do what they do.

The current issue is that with massive t-cell infiltration into tumor site comes tumor-associated macropahges which can be depleted by CSF1R inhibitor.

CD163hi macrophages are resistant to CSF-1(R) targeted therapies, and drive both primary and secondary immune resistance. We know that clinical trials testing CSF-1(R) targeted therapies have shown poor results to date, and that CSF-1R+ macrophages can be positively associated with response [5].

The CD163hi macrophage issue is so minor in comparison of massive and sustainable t-cell infiltration triggered by DCVax-L.

High frequency of CD163hi macrophages correlates with higher risk of relapse, predicts poor response to ICI, and poor survival across different (sub)types of cancer.

CD163hi macrophages were also infiltrating two progressing lesions in the patient I talked after she received tens of billions of TCR-T cells (plus an anti-PD-1).

Refs:
1 https://www.nejm.org/doi/full/10.1056/NEJMoa1609279
2 https://aacrjournals.org/cancerimmunolres/article/10/8/932/707173/Adoptive-Cellular-Therapy-with-Autologous-Tumor
3 https://aacrjournals.org/cancerdiscovery/article/11/2/282/2772/Somatic-HLA-Class-I-Loss-Is-a-Widespread-Mechanism
4 https://academic.oup.com/cei/article/180/2/255/6422173
5 https://jitc.bmj.com/content/10/5/e003890