Research Highlights
Nature Reviews Cancer | https://doi.org/10.1038/s41568-018-0094-4 | Published online xx xx xxxx
I M M U N OT H E R A P Y
Radiation promotes systemic responses
Radiation therapy can enhance
the systemic antitumour responses
(abscopal responses) induced by
The findings
anti-CTLA4 antibodies, as shown by
highlight a preclinical studies. However, it was
role for the unclear how effective these induced
systemic responses are against tumours
anti-CTLA4
unresponsive to CTLA4 blockade
antibody alone. Now, Formenti, Demaria and
ipilimumab colleagues report in Nature Medicine
that a combination of radiotherapy
when com­
and CTLA4 blockade induced systemic
bined with antitumour T cells in patients with
radiotherapy non-small-cell lung cancer (NSCLC)
who did not respond to CTLA4 blockade
in treating
alone, possibly through radiotherapy-
metastatic induced upregulation of a protein
NSCLC recognized by expanded T cell clones.
The findings highlight a role for the
anti-CTLA4 antibody ipilimumab when
Credit: Lara Crow/Springer Nature Limited
Nature Reviews | Cancer
combined with radiotherapy in treating
metastatic NSCLC.
Thirty-nine patients with NSCLC
whose tumours had progressed
after prior systemic treatment were
enrolled in a clinical trial to evaluate
radiotherapy in combination with
ipilimumab. Of those, 21 (54%)
completed four cycles of ipilimumab
and were evaluated by Response
Evaluation Criteria In Solid Tumours
(RECIST).
At day 88, two patients had a
complete response, five had a partial
response and five had stable disease —
objective responses were seen in 18%
of enrolled or 33% of evaluable patients
and disease control was seen in 31% of
enrolled patients.
The authors analysed a panel of
soluble markers and immune cells in the
tumour tissue and peripheral blood of
the patients who completed treatment
by comparing levels at baseline and at
day 22. Notably, radiotherapy induction
of interferon-β (IFNβ) correlated with
abscopal response to the combination
therapy — in the patients who
responded to treatment, serum IFNβ
levels were significantly increased at
day 22 (after radiation therapy); those
who had stable disease had a significant
increase but it was less than in those
who responded; and patients who
progressed had no significant increase.
Next, T cell receptor (TCR) sequencing
established that a significant number
of T cell clones were expanded in
peripheral blood at day 22 compared
with baseline in patients with complete
or partial responses compared with
patients with stable disease or who
progressed. Furthermore, levels of
IFNβ after radiotherapy combined
with the changes in the TCR repertoire
had the highest predictive value of
response.
Examination of the tumour specificity
of the expanded T cell clones in one
patient with a complete response
indicated that this patient had
tumour-infiltrating lymphocytes
that matched the expanded clones.
The authors also identified two
expanded T cell clones in the periphery
in this patient, both of which recognized
a neoantigen derived from a protein,
karyopherin α2, thought to be
upregulated during radiotherapy.
Thus, the authors hypothesize that
radiotherapy may increase expression
of immunogenic mutations in the
tumour, leading to activation of T cells
that induce IFNβ, suggesting a possible
future role for combination therapy with
ipilimumab and radiotherapy.
Jordan Hindson
Original article Formenti, S. C. et al.
Radiotherapy induces responses of lung cancer
to CTLA-4 blockade. Nat. Med. 24, 1845–1851
(2018)
Further reading Ngwa, W. et al. Using
immunotherapy to boost the abscopal effect.
Nat. Rev. Cancer 18, 313–322 (2018)