Immune Checkpoint Inhibitors: The New Breakout Stars in Cancer Treatm | Page 5

PD-1 and PD-L1 inhibitors have been the favored
starlets of the oncology world because, in addition
to more durable responses in some patients, the
treatment is more tolerable than with chemotherapy.
Also, the response with PD-1/PD-L1 blockade is
relatively rapid, compared with other immunotherapies,
including ipilimumab, IL-2, and allogeneic stem cell
transplantation, taking only 8-12 weeks to develop
tumor-specific T-lymphocyte activity rather than
months.
They have also provided hope for patients with cancers
that have otherwise appeared to resist treatment and
have had few therapeutic advances, such as squamous
lung cancers and metastatic melanoma.
However, their performance can be unreliable, based
on an inability to identify who will respond because
PD-1 expression levels and clinical response to PD-1
inhibitors do not appear to be linked; in addition,
they can have a potentially short-lived response and
high levels of toxicity linked to autoimmune processes
that are often irreversible, such as decreased thyroid
function.9,10 PD-1 inhibitors are considered less toxic
than CTLA-4 inhibitors; however, adverse effects with
any drug can cause treatment discontinuation and lower
therapy penetrance into the patient population.
So, although we love their performances when they’re
on target, we cannot rely on these relatively young stars
to consistently deliver and to satisfy the audience. How
do we save our investment and continue to make these
stars available to their fans?
Where to From Here?
Why not utilize the consistently performing character
stars in the form of standard treatment, bring
back older stars such as cytokines, and introduce
newer stars as they are discovered? Treatments with
traits complementary to the immune checkpoint
inhibitors could be paired with these newer therapies.
Combination therapies that have an immunotherapy
component might result in a higher rate of and longer
response, by directly stimulating cytotoxic T cells,
blocking tumor-expressed immunoinhibitory factors,
inhibiting regulatory T cells, blocking the inhibition of
natural killer (NK) cell activity, or blocking the activity
of soluble factors produced by stromal myeloid and
mesenchymal cells.8

Combination Therapies
Initial research combining immune checkpoint
inhibitors with other therapies has involved PD-1 and
PD-L1 inhibitors, administered in conjunction with
cytotoxic chemotherapy, radiation therapy, CTLA4 inhibitors, or small-molecule inhibitors such as
the VEGFR tyrosine kinase inhibitors sunitinib and
paxopanib.10 Based on what we have learned with
immune checkpoint inhibitor monotherapy, the
blockade of PD-1 or PD-L1 has served as the backbone
of a number of these trials because of their more
subtle role in maintenance of peripheral tolerance and
regulation of inflammation. However, the use of an
anti-PD-1 agent specifically as the primary therapeutic
might have the advantage of fewer side effects, while
producing good response rates in more tumor types.10

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Although we love their
performances when they’re
on target, we cannot rely on
these relatively young stars
to consistently