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Thursday, December 27, 2018

Some Thoughts on Immunotherapy of Solid Tumors

A) CAR CD28

The question is why CARs don’t infiltrate solid tumors & why they don’t proliferate as much when targeted against a solid tumor as they do when targeted against a leukemia or lymphoma. I think it could be because their CD28 doesn’t interact with cd80/86 so they become anergic. The story is that proteins from leukemias are presented by antigen presenting cells, but when cells in solid tumors die, their proteins are not processed by peripheral blood leukocytes (PBLs) but rather stay in the poorly vascularized tumor and are metabolized by other cancer cells.

If this is the problem, then there are well established approaches to overcoming it

1) Ablation. If there are multiple tumors then killing many cells in one (with x-rays or liquid nitrogen or whatever) is useful. This causes inflatimation and releases large amounts of tumor antigens attracting the attention of PBLs which then present the antigens

2) Vaccination. The targets of CARs are very well defined. If the CARs are not activated by tumors, they can be activated by inoculating with target antigens and adjuvant.

3) In vitro activation. The CARs can be activated in vitro before they are infused. The idea is to infuse memory CARs not resting CARs. An advantage of in vitro activation is that one doesn’t have to worry about damaging test tubes’ livers. It could be done with target antigen, IL15-IL15rAlpha, and anti CD-28 (maybe on beads or something because one better not infuse anti-CD28 into people).

I wonder how many groups are trying each of these approaches. I think it should be a large number.

B) Ordinary CD8 killers.

I know of three trials at the NCI each of which adds to anti PD1: Kevin Conlon adds anti-PD1, the Geraldine H. O'Sullivan Coyne, adds anti-CTLA4 and the Tim Gretens adds ablation and anti-CTLA4. I think some might get together and ablate and add IL15. They might also add an antibody such as anti-mesothelin.

There is also a much simpler way to redirect a TCR to a target – a bifunctional antibody with anti target and anti CD3. Amgen is trying this with the melanoma maturation antigen. I never got the logic of CARs – why does the modified TCR have to be a chimeric protein held together with amino bonds and not a CD£-anti-CD3 complex ? I do think that if one uses the anti-CD3 approach it is necessary to have activated CD8 killers, which can be obtained with any antigen especially including inoculation with non self HLA. Here the variable chains of the TCR don’t matter as the cells are targeted with anti CD3.

C) NK cells

There is a group trying trifunctional targeting antibody, anti FC III (also known as CD16) and IL-15 ClinicalTrials.gov Identifier: NCT03214666. I don’t see why just plain gamma globulin with Fc (which sticks to Fc III and Fc IV) and systemic IL-15 wouldn’t work as well. In any case, it seems to me that if one is causing NK cell proliferation and Fc IV expression with IL15, then one really wants a tumor specific monoclonal (again anti Mesothelin or maybe something new like the Hopkins (Vogelstein group) anti KRAS g12v presented with HLA A2 monoclonal.

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