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CAR-T project concept map

Work in progress

Mouse Model Characteristics

24 March 2023

1. Tumor difference between meropenem and vehicle gps

2. No difference in peripheral blood B cell counts or CAR-T counts

What are the key microbiome players?

Methods to identify:

Decontamination on top of meropenem

Microbiome

What are some relevant good bacteria?

Good bacteria are key

Depletion of good bacteria affects CAR-T response in following ways:

1. Loss of important metabolites in serum

2. Loss of co-stimulatory ligands

3. Increase of suppressive ligands

Replenish good bacteria

Validation

Bacterial add-back

Use 16S qPCR to identify species-level information

Followed by full length sequencing to identify strain level information

Method to narrow down specific bacterial contribution

Consortia

Use 1:1 ratios of various bacteria in add-back experiment to validate contribution of specific species versus multiple species

Control

Use non-functional mutant to validate effect of bacteria

Individual bacteria

Experiments that show direct involvement of bacteria

Mechanism

Metabolomics

Metabolites

Serum metabolomics

Which metabolites should be lost based on literature?

Bacteria supernatant improves CAR-T cell function/phenotype

Shotgun sequencing?

What are some stimulatory ligands versus ligands that support activation and differentiation of suppressive ligands?

Ligands

What are some relevant bad bacteria?

Bad bacteria are key

Expansion of bad bacteria in absence of good bacteria drives poor response

Depletion using narrow-spectrum antibiotics

Validation

Consortia

Individual bacteria

How are bad bacteria known to suppress T cells in literature?

Mechanism

Which bacterial metabolites suppress T cells?

Metabolites

Which bacterial ligands suppress T cells?

Ligands

What are some CAR-T-related differences?

No functional issue since peripheral blood B cell recovery on day 21 is same between both groups

CAR-T

Are CAR-T infilterating tumors in both groups similarly?

Tumor infiltration

CAR-T trafficking is not affected

Yes

TME elements

Tumor

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