US 2024/0402183 A1Published application

Spatial metric measurement methods for multiplex imaging and uses in tumor sample analysis

AssigneesCedars-Sinai Medical Center, BC Cancer, Part of the Provincial Health Services Authority

InventorsAlexander Xu, Akil Merchant, Anthony Colombo, Tomohiro Aoki, Aixiang Jiang, Christian Steidl

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Abstract

Spatial analysis methods based on nearest neighbor analysis are provided of specific regions of tissue to describe cancer states and develop biomarkers to predict outcomes. In various embodiments, the spatial analysis methods involve an interaction radius to computationally isolate local interactions and prevent the data from being influenced by cells that are very far away. Thereby, spatial analysis of cancer tissue can be quickly and consistently performed in an automated fashion to focus on tumor-immune cell biology, which occurs at a localized level.

Claims20

Dependent claims

A method of providing an enrichment score for a target cell in a tissue sample, the enrichment score representing enrichment of a selected cell type around the target cell, the method comprising:

a. measuring a distance from the target cell to its nearest cell or to each one of its nearest two or more cells of the selected cell type within a predetermined radius, optionally via an image of the tissue sample;
b. scaling the measured distance via division by the predetermined radius, thereby obtaining a scaled distance, and if the measuring in step a comprises measuring the distance to each one of the nearest two or more cells, then further averaging the scaled distance to obtain an average scaled distance;
and
c. performing an inverse operation on the scaled distance or the average scaled distance, thereby obtaining an inverted scaled distance from the target cell to its nearest cell or nearest two or more cells of the selected cell type as the enrichment score for the target cell;
and
d. optionally displaying, on a computer screen, the enrichment score based on the inverted scaled distance.

3 more elements

A method for treating a refractory or relapsed classical Hodgkin lymphoma (r/r cHL) in a human subject, the method comprising:

(a) obtaining two or more enrichment scores for a target cell (also called a home cell) in a biopsy sample from the human subject, each enrichment score representing enrichment of a selected cell type (also called an enriching cell type) around the target cell (also called home cell), wherein the target cell (that is, the home cell) comprises a Hodgkin and Reed Sternberg (HRS) tumor cell, and wherein the selected cell types (that is, the enriching cell types) comprise CXCR5+ HRS tumor cells, PD1+CD4+ T cells, CD68+ macrophages, and CXCR5+ B cells, and wherein each enrichment score is an inverse of an average of scaled distances from the target cell (that is, the home cell) to its nearest two or more cells of respective selected cell type within a predetermined radius, such that the inverse results in a greater enrichment score for a smaller averaged scaled distance compared to that for a larger averaged scaled distance;
(b) calculating a linear predictor score (LPS) for the biopsy sample, wherein each LPS is a linear, weighted combination of the enrichment scores representing enrichment of the four different selected cell types calculated from (a), using an equation:
LPS
⁢
(
X
)
=
∑
j
a
j
⁢
X
j
wherein Xj is the enrichment score representing enrichment of a selected cell type j around the target cell or is a mean, median or average of top 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the highest enrichment scores calculated for a plurality of the target cell type in the biopsy sample;
and aj is a scaling factor or weight for the selected cell type j, optionally aj being within 0 to 1;
and
(c) calculating a probability that the human subject is at low-risk or at high-risk of salvage treatment failure, optionally salvage treatment failure comprising further relapse, using an equation:
P
⁡
(
X
)
=
ϕ
⁡
(
LPS
⁡
(
X
)
;
μ
1
,
σ
1
2
)
ϕ
⁡
(
LPS
⁡
(
X
)
;
μ
1
,
σ
1
2
)
+
ϕ
⁡
(
LPS
⁡
(
X
)
;
μ
2
,
σ
2
2
)
,
wherein:
for calculating the probability of low-risk of salvage treatment failure, Ø(LPS(X);
μ1, σ12) is a Phi value when the calculated LPS from step (b) is applied in a normal distribution function with mean μ1 and variance σ12 from a first r/r cHL patient population known to have no salvage therapy failure or known with low-risk of salvage therapy failure, and Ø(LPS(X);
μ2, σ22) is a Phi value when the calculated LPS from step (b) is applied in a normal distribution function with mean μ2 and variance σ22 from a second r/r cHL patient population with known salvage therapy failure or known high-risk of salvage therapy failure;
or
for calculating the probability of high-risk of salvage treatment failure, Ø(LPS(X);μ1,σ12) is a Phi value when the calculated LPS from step (b) is applied in a normal distribution function with mean μ1 and variance σ12 from the second r/r cHL patient population with known salvage therapy failure or known high-risk of salvage therapy failure, and Ø(LPS(X);
μ2, σ22) is a Phi value when the calculated LPS from step (b) is applied in a normal distribution function with mean μ2 and variance σ22 from the first r/r cHL patient population known to have no salvage therapy failure or known with low-risk of salvage therapy failure;
(d) classifying the human subject as at low-risk of salvage treatment failure if:
the calculated probability of low-risk of salvage treatment failure from step (c) is 0.8 or greater, or
the calculated probability of high-risk of salvage treatment failure from step (c) is less than 0.5, less than 0.4, less than 0.3, or less than 0.2;
or
classifying the human subject as at high-risk of salvage treatment failure if:
the calculated probability of high-risk of salvage treatment failure from step (c) is 0.8 or greater, or
the calculated probability of low-risk of salvage treatment failure from step (c) is less than 0.5, less than 0.4, less than 0.3, or less than 0.2;
and
(e) providing treatment to the human subject, wherein the treatment comprises salvage therapy comprising autologous stem cell transplantation (ASCT) or a combination of high-dose chemotherapy and the ASCT if the human subject is indicated as at low-risk of salvage treatment failure, or wherein the treatment comprises allogeneic bone marrow transplantation, a CD30 targeting treatment, and/or brentuximab vedotin if the human subject is indicated as at high-risk of the salvage treatment failure.

88 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/680,481Filed 31 May 2024
Priority: 2 Jun 2023
Published: 5 Dec 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

G01N 33/5759
Involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins,…:…
C12Q 1/6874
Methods for sequencing: involving nucleic acid arrays, e.g. sequencing by hybridisation
C12Q 1/6886
For diseases caused by alterations of genetic material: for cancer
G01N
Investigating or analysing materials by determining their chemical or physical properties