ASH News Daily 2017 - Issue 1 - A-10

Page A-10

ASH News Daily

Saturday, December 9, 2017

T R A N S P L A N T B I O L O GY

Targeting T Cell Exhaustion: Filling Up the T Cell Gas Tank
By Farrukh T. Awan, MD

he story of President Jimmy
Carter's fight with metastatic melanoma is well-known.
After being diagnosed with metastatic melanoma with disease in
the liver and multiple brain lesions, the prognosis for a typical
octogenarian would usually be
dismal. Enter PD-1 and PD-L1 targeting agents, which are remarkable in their ability to reverse the
immunosuppressive
phenotype
remained generally constant over the follow-up
period in both cohorts. All patients who tested
positive for anti-recombinant human hyaluronidase
antibodies at any point during the study were
negative for neutralizing antibodies.
In the SAWYER study, where previously
untreated patients with CLL were treated with
RITUXAN HYCELA or rituximab in combination
with FC, the incidence of treatment-induced/
enhanced anti-rituximab antibodies was 2.4%
in the RITUXAN HYCELA group vs. 6.7% in
rituximab group. The incidence of treatmentinduced/enhanced anti- recombinant human
hyaluronidase antibodies was 10.6% in the
RITUXAN HYCELA treatment arm. None of the
patients who tested positive for anti-recombinant
human hyaluronidase antibodies tested positive
for neutralizing antibodies.
The clinical relevance of the development
of anti-rituximab or anti-recombinant human
hyaluronidase antibodies after treatment with
RITUXAN HYCELA is not known.
6.3 Postmarketing Experience
The following adverse reactions have been identified
during post-approval use of rituximab-containing
products. Because these reactions are reported
voluntarily from a population of uncertain size, it
is not always possible to reliably estimate their
frequency or establish a causal relationship to
drug exposure.
* Hematologic: prolonged pancytopenia, marrow
hypoplasia, Grade 3-4 prolonged or lateonset neutropenia, hyperviscosity syndrome in
Waldenstrom's macroglobulinemia, prolonged
hypogammaglobulinemia
* Cardiac: fatal cardiac failure
* Immune/Autoimmune Events: uveitis, optic
neuritis, systemic vasculitis, pleuritis, lupus-like
syndrome, serum sickness, polyarticular arthritis,
and vasculitis with rash.
* Infection: viral infections, including progressive
multifocal leukoencephalopathy (PML), increase in
fatal infections in HIV-associated lymphoma, and
a reported increased incidence of Grade 3 and 4
infections
* Neoplasia: disease progression of Kaposi's
sarcoma.
* Skin: severe mucocutaneous reactions.
* Gastrointestinal: bowel obstruction and perforation.
* Pulmonary: fatal bronchiolitis obliterans and fatal
interstitial lung disease.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on human data, rituximab-containing
products can cause adverse developmental
outcomes including B-cell lymphocytopenia in
infants exposed to rituximab in-utero (see Clinical
Considerations). There are no available data on
RITUXAN HYCELA use in pregnant women to
inform a drug-associated risk of major birth defects
and miscarriage. In animal reproduction studies,
intravenous administration of a rituximab product to
pregnant cynomolgus monkeys during the period
of organogenesis caused lymphoid B cell depletion
in the newborn offspring at doses resulting in 80%
of the exposure (based on AUC) of those achieved
following a dose of 2 grams in humans. Reduced
fetal weight and increased fetal lethality were
observed following subcutaneous administration
of hyaluronidase human in mice at a dose > 2700
times higher than the human dose. Comparable
systemic exposure levels could occur in a
pregnant patient following accidental intravenous
administration of an entire vial of RITUXAN HYCELA
(see Data). Advise pregnant women of the risk to
a fetus.
Adverse outcomes in pregnancy occur regardless of
the health of the mother or the use of medications.
The background risk of major birth defects and
miscarriage for the indicated population is unknown.
The estimated background risk in the U.S. general
population of major birth defects is 2%-4% and of
miscarriage is 15%-20% of clinically recognized
pregnancies.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Observe newborns and infants for signs of infection
and manage accordingly.
Data
Human Data
Postmarketing data indicate that B-cell
lymphocytopenia generally lasting less than six
months can occur in infants exposed to rituximab
in-utero. Rituximab was detected postnatally in
the serum of infants exposed in-utero.
Animal Data
RITUXAN HYCELA for subcutaneous injection
contains rituximab and hyaluronidase human [see
Description (11)].

of T cells, providing them an opportunity to target various tumor
subtypes. For President Carter,
the control of his disease is an opportunity to continue his efforts to
eradicate Dracunculiasis (Guinea
worm disease), while for millions
of others it's an opportunity to
continue living healthy and productive lives, pursuing their goals
and dreams while actively fighting
cancer. From the cancer therapy
perspective, we can say that the
last decade in oncology belongs to
Rituximab Product:
* An embryo-fetal developmental toxicity study
was performed on pregnant cynomolgus
monkeys. Pregnant animals received rituximab
via the intravenous route during early gestation
(organogenesis period; post coitum days 20
through 50). Rituximab was administered as
loading doses on post coitum (PC) Days 20, 21
and 22, at 15, 37.5 or 75 mg/kg/day, and then
weekly on PC Days 29, 36, 43 and 50, at 20, 50
or 100 mg/kg/week. The 100 mg/kg/week dose
resulted in 80% of the exposure (based on AUC)
of those achieved following a dose of 2 grams in
humans. Rituximab crosses the monkey placenta.
Exposed offspring did not exhibit any teratogenic
effects but did have decreased lymphoid tissue
B cells.
* A subsequent pre-and postnatal reproductive
toxicity study in cynomolgus monkeys was
completed to assess developmental effects
including the recovery of B cells and immune
function in infants exposed to rituximab in utero.
Animals were treated with a loading dose of 0,
15, or 75 mg/kg every day for 3 days, followed
by weekly dosing with 0, 20, or 100 mg/kg dose.
Subsets of pregnant females were treated from
PC Day 20 through postpartum Day 78, PC
Day 76 through PC Day 134, and from PC Day
132 through delivery and postpartum Day 28.
Regardless of the timing of treatment, decreased
B cells and immunosuppression were noted in the
offspring of rituximab-treated pregnant animals.
The B-cell counts returned to normal levels,
and immunologic function was restored within
6 months postpartum.
Hyaluronidase Human:
* In an embryo-fetal study, mice have been dosed
daily by subcutaneous injection during the period
of organogenesis with hyaluronidase human at
dose levels up to 2,200,000 U/kg, which is > 2700
times higher than the human dose. The study
found no evidence of teratogenicity. Reduced fetal
weight and increased numbers of fetal resorptions
were observed, with no effects found at a daily
dose of 360,000 U/kg, which is > 450 times higher
than the human dose.
* In a peri-and post-natal reproduction study, mice
have been dosed daily by subcutaneous injection,
with hyaluronidase human from implantation
through lactation and weaning at dose levels up
to 1,100,000 U/kg, which is > 1,300 times higher
than the human dose. The study found no adverse
effects on sexual maturation, learning and memory
or fertility of the offspring.
8.2 Lactation
There are no data on the presence of rituximab
or hyaluronidase human in human milk, the effect
on the breastfed infant, or the effect on milk
production. However, rituximab is detected in the
milk of lactating cynomolgus monkeys, and IgG is
present in human milk. Since many drugs including
antibodies are present in human milk, advise a
lactating woman not to breastfeed during treatment
and for at least 6 months after the last dose of
RITUXAN HYCELA due to the potential for serious
adverse reactions in breastfed infants.
8.3 Females and Males of Reproductive
Potential
Rituximab-containing products can cause fetal
harm [see Use in Specific Populations (8.1)].
Contraception
Females
Females of childbearing potential should use
effective contraception while receiving RITUXAN
HYCELA and for 12 months following treatment.
8.4 Pediatric Use
The safety and effectiveness of RITUXAN HYCELA
in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of subjects in the SABRINA,
MabEase, and SAWYER studies, 37% were 65
and over, while 10% were 75 and over. No overall
differences in safety or effectiveness were observed
between these subjects and younger subjects, and
other reported clinical experience has not identified
differences in responses between the elderly and
younger patients, but greater sensitivity of some
older individuals cannot be ruled out.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Severe Mucocutaneous Reactions
Advise patients to contact their healthcare provider
immediately for symptoms of severe mucocutaneous
reactions, including painful sores or ulcers on the lips
or mouth, blisters, peeling skin, rash, and pustules
[see Warnings and Precautions (5.1)].

immune checkpoint inhibitors.
From the 2006 seminal report in
Nature by Dr. Rafi Ahmed and colleagues on restoring T cell function in chronic viral infection, the
study of checkpoint inhibitors
has progressed rapidly in oncology. Multiple new ligands have
been identified, which can now
be effectively targeted with generally well-tolerated agents. Many of
these agents are approved to target
various indications of solid tumors
and hematologic malignancies.

Hepatitis B Virus Reactivation
Advise patients to contact their healthcare provider
immediately for symptoms of hepatitis including
worsening fatigue or yellow discoloration of skin or
eyes [see Warnings and Precautions (5.2)].
Progressive Multifocal Leukoencephalopathy (PML)
Advise patients to contact their healthcare provider
immediately for signs and symptoms of PML,
including new or changes in neurological symptoms
such as confusion, dizziness or loss of balance,
difficulty talking or walking, decreased strength
or weakness on one side of the body, or vision
problems [see Warnings and Precautions (5.3)].
Hypersensitivity and Other Administration Reactions
Inform patients about the signs and symptoms of
hypersensitivity and administration-related reactions.
Advise patients to contact their healthcare provider
immediately to report symptoms of administrationrelated reactions including dizziness, nausea, chills,
fever, vomiting, diarrhea, urticaria, angioedema,
breathing problems, or chest pain [see Warnings
and Precautions (5.4)].
Tumor Lysis Syndrome (TLS)
Advise patients to contact their healthcare provider
immediately for signs and symptoms of tumor lysis
syndrome such as nausea, vomiting, diarrhea, and
lethargy [see Warnings and Precautions (5.5)].
Infections
Advise patients to contact their healthcare provider
immediately for signs and symptoms of infections
including fever, cold symptoms (e.g., rhinorrhea or
laryngitis), flu symptoms (e.g., cough, fatigue, body
aches), earache or headache, dysuria, cold sores,
and painful wounds with erythema [see Warnings
and Precautions (5.6)].
Cardiovascular Adverse Reactions
Advise patients of the risk of cardiovascular
adverse reactions, including ventricular fibrillation,
myocardial infarction, and cardiogenic shock.
Advise patients to contact their healthcare provider
immediately to report chest pain and irregular
heartbeats [see Warnings and Precautions (5.7)].
Renal Toxicity
Advise patients of the risk of renal toxicity. Inform
patients of the need for healthcare providers
to monitor kidney function [see Warnings and
Precautions (5.8)].
Bowel Obstruction and Perforation
Advise patients to contact their healthcare provider
immediately for sign and symptoms of bowel
obstruction and perforation, including severe
abdominal pain or repeated vomiting [see Warnings
and Precautions (5.9)].
Embryo-Fetal Toxicity
Advise a pregnant woman of the potential risk
to a fetus. Advise female patients that rituximab
containing products can cause fetal harm if taken
during pregnancy and to use effective contraception
during treatment with RITUXAN HYCELA and for
at least 12 months after the last dose of RITUXAN
HYCELA. Advise patients to inform their healthcare
provider of a known or suspected pregnancy [see
Warnings and Precautions (5.11) and Use in Specific
Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during treatment
with RITUXAN HYCELA and for 6 months after the
last dose [see Use in Specific Populations (8.2)].

RITUXAN HYCELA™
[rituximab and
hyaluronidase human]
Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco,
CA 94080-4990
U.S. License No.: 1048

RITUXAN HYCELA™ is
a trademark of Biogen.
Jointly marketed by: Biogen
and Genentech USA, Inc.
©2017 Biogen and
Genentech USA, Inc.
RSC/062017/0061

06/17

However, despite the promising activity observed with these agents,
long-term sustained disease control
remains elusive for many patients.
These and other issues will be covered in an extremely important and
timely scientific session, "Targeting
T Cell Exhaustion," organized by
the Scientific Committee on Transplantation Biology and Cellular
Therapies, taking place today at
9:30 a.m. in the Murphy Ballroom
1-2 of the Georgia World Congress
Center. The session will provide a
comprehensive review of the state
of the immune checkpoint inhibitor
field and help identify significant
challenges and deficiencies in our
understanding.
The session will be chaired by
Dr. W. Nicholas Haining of the
Dana-Farber Cancer Institute. Dr.
Rafi Ahmed of Emory University
Vaccine Center on "T Cell Memory
and Exhaustion". He will review
the physiology of T cell response to
acute and chronic viral pathogens
and tumors, and the variability of
functionally distinct subsets of exhausted T cells. This can potentially
result in differential response to
these therapies and guide the development of rationally designed trials. Other eminent speakers include
Dr. Arlene H. Sharpe of Harvard
Medical School, who will discuss
the "Biology of PD-1 Checkpoint
Blockade" and provide updates on
the recent updates in our understanding of the PD-1 pathway function in cancer. She will also inform
us of the role of this pathway in regulating T cell activation, tolerance,
resolution of inflammation, and
anti-tumor immunity. Additionally,
Dr. Dario A. Vignali of University
of Pittsburgh School of Medicine
will discuss the "Biology of LAG3
Checkpoint Blockade" and its role
in T cell exhaustion, immune regulation, and T-reg modulation, with
a specific focus on mouse models
of cancer and autoimmunity, and
in a variety of human malignancies.
Moreover, he will discuss how this
ligand can impact the responsiveness to immunotherapy.
The importance and timeliness
of this session cannot be overstated,
and we welcome your participation, but don't lose heart if you miss
it today as it will be offered again
tomorrow at 9:30 a.m. in the same
location. Please join us in this exciting session that puts the spotlight
on T cell function and opportunities for reversal of exhaustion.
Dr. Awan indicated no relevant conflicts of interest.

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 1