Immune Checkpoint Inhibitors: The New Breakout Stars in Cancer Treatm | Page 6

In preliminary results from a trial that combined
atezolizumab (anti-PD-L1) and chemotherapy
(nab-paclitaxel) to treat TNBC, the ORR of 67% for
the 9 patients that had not been previously treated
is higher than any ORR previously observed for this
cancer. The overall ORR was 42%, which is also high
for metastatic TNBC. Based on these results, a new
trial (NCT02425891) was initiated for previously
untreated patients.
Important considerations for combination
therapy with chemotherapy are:11
• Chemotherapy dose:
- Lower-than-standard doses that do not result
in T cell depletion might augment an
immunotherapeutic response
• Timing:
- Many cytotoxic chemotherapy agents target
rapidly dividing cells,8 and need to determine
appropriate timing to control the tumor and
prolong survival12
• Mechanism of action:
- Cytotoxic chemotherapy might also augment
an immunotherapeutic response, and some
chemotherapy regimens might prime the
immune system to respond to checkpoint
inhibition10
- At the same time, some chemotherapy
regimens that deplete proliferating
lymphocytes might affect the effectiveness
of ipilimumab and nivolumab that facilitate
the activation and proliferation of tumor
infiltrating lymphocytes10
In addition, the recently released Guideline on evaluation
of anticancer medicinal products in man,13 by the
European Medicines Agency, describes three possible
scenarios for investigating the combination
of a checkpoint inhibitor and chemotherapy:
1. Uni-enhancement: when one of the agents has no
or minimal anti-tumor activity on its own but enhances
that of the other agent; non-clinical trials should be
conducted for the first agent, and a phase II
comparative trial should also be conducted.
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2. Co-enhancement: when both agents in the
combination have anti-tumor activity on their own,
and this activity increases when they are used in
combination; phase II trials should compare the
combination with each of the agents as monotherapy.
3. Synthetic lethality: neither agent has anti-tumor
activity on its own, but they have potent activity
when combined.
With the increasing use of immune checkpoint inhibitors
as cancer treatments, radiation oncologists have observed
unexpected abscopal effects in these patients who are
concomitantly treated with radiation therapy.14,15 It has
been hypothesized that a tumor can be converted into
an in situ individualized vaccine by radiation. This might
explain the synergy between radiation and immune
checkpoint inhibitors.
Radiation might be particularly useful for the patients
who do not have pre-existing antitumor immunity,
because it removes the obstacles that hinder antitumor
T cell activation and function and induces antitumor
T cells that complement the immune checkpoint
inhibitor activity.14
Tumor cell death that is induced by radiation can activate
tumor-specific immune responses by increasing the
supply of tumor-specific antigens and attracting immune
cells to the tumor microenvironment.11 Furthermore,
the tumor cell phenotype is modulated, and the cells
become more susceptible to immune-mediated death,
by cytotoxic T cells. Experimental evidence also suggests
that radiation induces immunogenic cell death and
promotes T cell recruitment and function with the tumor
microenvironment.14
Compared with standard treatment, combined
nivolumab and radiation therapy in patients with
melanoma that had metastasized to the brain resulted
in better disease control (91% after 6 months and 85%
after 12 months) and prolonged overall survival (OS).16
Historically, patients with melanoma brain metastases
survive an average of 4-5 months; in this study, the
median OS was 11.8 and 12.0 months from initiation
of stereotactic radiation and nivolumab, respectively, in
patients with unresected disease, and the median OS
was not reached for patients with resected disease. There
were no treatment-related neurologic toxicities or scalp
reactions except for one patient who experienced grade 2
headaches, which were managed with steroid treatment.