Discussion
There is a paucity of therapeutic options and no validated standard of
care for rHGG. This retrospective series demonstrated ICI with
concurrent re-irradiation using SBRT can be safely delivered in rHGG.
Preclinical data provides a rationale for evaluating ICI in this
clinical setting (21,
24). The statistically significant
increase in post-treatment tumor volumes identified within our cohort
may in part have reflected a component of pseudoprogression related to
ICI. Prior studies associate ICI treatment response with a preceding
increase in tumor volume related to intratumoral immune cell
infiltration, resulting in a transient inflammatory reaction
(25).
Understanding ICI response requires further elucidation of the
intratumoral milieu and systemic immune response
(26-31). Several studies support
preoperative ICI enhance expression of chemokine transcripts including
interferon-γ, increase immune cell infiltration, and augment T cell
receptor clonal diversity, but with conflicting clinical results
(32, 33).
One putative explanation for suboptimal immune response is the high rate
of lymphopenia observed in HGG patients, with one group reporting that T
cells are available in this population but are sequestered in the bone
marrow (34).
The aforementioned studies provide a rationale for optimizing
immunotherapeutic efficacy through its implementation in an
immunologically favorable setting, such as priming the immune system to
tumor-specific antigens. RT may improve ICI effects by increasing the
quantity and diversity of intracellular peptides, increasing MHC class I
expression, and promoting T cell recruitment and infiltration
(20-22,
35-38). Technological advancements in the
delivery of SBRT allow for highly conformal treatments that
significantly reduce the toxicity associated with re-irradiation in
other disease sites (16). Several studies
show an improvement in functional status and discontinuation of
corticosteroid usage following SBRT monotherapy with a low risk of late
central nervous system toxicity (14,
15, 17,
18, 39).
Additionally, SBRT dose-fractionation schemes may be more effective than
conventionally fractionated RT with regard to augmenting immune
responses (22,
40). This option also allows RT
completion within one to five treatments, which is convenient for
patients.
A closer look at this cohort notes several limitations that could be
considered in future studies geared towards optimizing a response. Most
patients had multiple recurrences and subsequently received various
systemic treatments either on or off clinical trials. There was a mean
of 4.5 lines of treatment administered with ICI+SBRT therapy given as
the last line in 8 of these patients. There is a possibility that these
prior treatments negatively impacted the ability to prime the immune
system, and a more robust response may be seen if treated with ICI +
SBRT at first recurrence. Patients were treated without knowing PD-L1
expression status. A few reports show higher response rates with
increased expression in other malignancies
(41), however the prognostic value of
PD-L1 for HGG is still under investigation. While foundational analyses
were available, advanced correlation studies were limited by the cohort
size. Two-thirds of the patients in this cohort were on dexamethasone
while receiving ICI which may interfere with the ICI efficacy.
The optimal treatment approach for patients with rHGG continues to be an
area of ongoing investigation. This small retrospective study suggests
ICI can be safely given concurrently with re-irradiation using SBRT for
patients with rHGG. These initial findings support evaluating whether
optimizing conditions for combinatory ICI + SBRT approaches may lead to
favorable clinical responses, or whether attention should be turned to
other therapeutic avenues to address this unmet need in neuro-oncology.