Decreasing the Immune System in Immunotherapy: How to Mitigate CRS

Brendon Davis, University of Washington, Molecular Biology Major

Background & Results Experimental Approach

What is CAR T-Cell Therapy?1
Is this therapy effective?
From Turtle et al2:
CAR-T Cell Therapy Results in Relatively
Favorable Rates of Survival
CR=complete remission patients, PR=partial
remission patients, SD/PD=stable/progressive
disease patients.
Chronic Lymphocytic Leukemia (CLL)3
What is it?
Special white blood cells called B
cells are an integral part of the
human immune system, but in CLL
the replicate rapidly, displacing
normal B cells and putting an
individual at greater risk of
infections or other threatening
symptoms.
Higher levels of CAR-T cells (y-axis) are
correlated with clearing of disease
Figure C refers to patients who did or did not come up as
negative for disease in bone marrow. Figure D shows
patients who did or did not have detectable malignant IGH
sequences in their marrow.
Symptoms of CLL How does ibrutinib help?
 Enlarged lymph nodes  Inhibits Bruton’s tyrosine
• Patients will be selected from individuals with
 Frequent infections kinase (BTK), a protein in B CLL who have been found to be resistant to
 Fever cells. BTK signaling is needed
 Abdominal pain or fullness for B cells to grow and divide.
ibrutinib, a common chemotherapeutic drug.
 Night sweats  May help to move cancerous B • The patients will be randomly split into two
 Tiredness cells out of locations where
 Unexpected weight loss they can grow more easily like
groups, both being administered CAR T cell
 Easy bruising and bleeding the lymph nodes, bone therapy but one group receiving regular small
marrow, and other organs.
doses (10-20% of the dose for grade 4 CRS) of
immunosuppressant corticosteroids in
conjunction and following CAR-T cell infusion.
CRS: a Dangerous Side Effect
• All patients will undergo the procedure
One of the most prominent outlined in the blue flowchart, left, with
side effects of CAR-T cell deviations in treatment due to ethical issues
therapy is cytokine release according to the green flowchart, left.
syndrome (CRS), in which
immune cells release too • The patients will be constantly monitored for
many signaling molecules CRS and graded according to Lee et al.5
called cytokines and cause • The subjects will be scored on change in
an overactive immune tumor size (via computed tomography scans),
response. This figure4 (right) CRS occurrence (diagnosed and scored with
shows the physical effects of
CRS. the methods in Lee et al.), and survival
(A) shows max temperature of individuals with severe and (progression free and total).
non-severe CRS (sCRS and nCRS, respectively). (B) shows
changes in cytokine concentration during treatment.

Hypothesis Specific Aims Expected Outcomes

Instances of cytokine release syndrome may be
reduced without reducing the efficacy of CAR-T cell
therapy by administering small doses of
corticosteroids, a group of immunosuppressant
molecules, in parallel with normal therapy.
Significance
CAR-T cell therapy is a promising method of
cancer treatment, but it has side effects like CRS
which prevent it from being generally considered as
a safe therapy. 83% of patients in Turtle et al.
developed CRS. If we can find a way to decrease
instances of dangerous side effects, CAR-T cell
therapy can move forward in clinical trials more
quickly.
• Investigate if low doses of corticosteroid treatment can
decrease CRS and its symptoms in CLL patients.
• Tested for by grading patients for CRS and
comparing steroid-receiving group to control.
• Determine if the CRS can be adequately mitigated
without decreasing the efficacy of CAR-T cell therapy.
• Comparing survival between those who are
receiving immunosuppressant and those who
are not should illuminate if this is a valid
method to avoid CRS. If the hypothesis for this experiment holds true, the results should show something similar to
those in the above graphs, with CRS occurrence significantly lower in the corticosteroid-
• Gather more data of CAR-T cell therapy and its side receiving group than the control group, but overall survival similar in the two groups. It should
effects in CLL patients. be noted that these are ideal results, and it would not be surprising to see lower survival in the
• Both the control and experimental groups will group receiving supplemental steroids, since these may impact the ability for the CAR-T cells to
provide valuable data on survival, CRS, and attack the tumor. The degree to which this effect may occur is of question.
cytotoxicity rates.
Works cited
1“Simmons Cancer Center Researchers Part of Historic CAR-T Breakthrough.” UT Southwestern Medical
Center, www.utsouthwestern.edu/newsroom/articles/year-2018/simmons-car-t.html.

2Turtle,
et al. Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific
Chimeric Antigen Receptor–Modified T Cells After Failure of Ibrutinib. doi:10.1200/JCO.2017.72.8519.

3“WhatIs Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma?” CLL & SLL Treatment Option |
IMBRUVICA® (Ibrutinib), www.imbruvica.com/cll/what-is-chronic-lymphocytic-leukemia.

4Davila,
et al. “Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute
Lymphoblastic Leukemia.” Molecular Therapy, vol. 22, 2014, doi:10.1016/s1525-0016(16)35779-3.

5Lee,DW, et al. “Current Concepts in the Diagnosis and Management of Cytokine Release
Syndrome.” Blood, vol. 126, no. 8, 2015, pp. 1048–1048., doi:10.1182/blood-2015-07-656918.