Enhancement of immune response by combining immune checkpoint blockade and radiation in patients with recurrent / refractory malignant lymphoma (re-directing the immune system).

After 2 - 3 lines of standard therapy, patients with recurrent / refractory
malignant lymphoma have a dismal prognosis. Immune checkponit blockade is one
of the remaining options and has shown encouraging results. Best results are
seen in malignant lymphomas with 9p24.1 amplification. This 9p24.1
amplification contains several genes of which PDCD1LG1 (encoding programmed
cell death 1 ligand 1) and PDCD1LG2 (encoding programmed cell death 1 ligand
2) are responsible for immune checkponit resistance.
Although malignant lymphomas with 9p24.1 amplification and also malignant
lymphomas without this amplification (albeit at a lesser extent) are sensitive
for immune checkpoint blockade, in the end they become resistant. Mainly case
reports have shown that this resistance can be overcome by irradiating (part
of) the tumour bulk.
Tumour cell disruption by radiation generates a surplus of neo-antigens that
enhances the effect of immunotherapy in solid malignancies as well as malignant
lymphomas. The hypothesis is that the combination of immune checkpoint
inhibitors and radiation will lead to better responses and longer survival in
patients with recurrent / refractory malignant lymphoma, compared with either
modality given alone.

This translational study focusses on the altered / improved immune response
triggered by the addition of radiation to immune checkpoint blockade therapy.
The study is investigative in nature.

Main study parameters/endpoints:
a) Alteration / increase in interferon I and II (INF I and II) signatures in
blood, measured 3 weeks after radiotherapy and after every 3 consecutive
courses of immune checkpoint blockade (ICB). It is anticipated that the
addition of radiotherapy will lead to an extra / more pronounced response.
b) [18F]FDG PET-CT response 3 weeks after radiotherapy and after every 3
consecutive courses of ICB, related to the presence of 9p24.1 amplification. It
is expected that lymphomas that harbour a 9p24.1 amplification and therefore an
overexpression of PD-L1 will be more sensitive to (radio-) ICB therapy
resulting in a more pronounced response.
c) Changes in ctDNA, based on the presence of tumour-specific somatic genomic
characterizations of the lymphoma; reflecting lymphoma activity or tumour cell
death, measured 3 weeks after radiotherapy and after every 3 consecutive
courses of ICB. After an initial increase, a larger decrease in ctDNA is
expected in the irradiated group.

The study population consists out of 2 groups, 10 patients each:
A. 10 patients with recurrent / refractory 9p24.1 amplified malignant lymphomas
eligible for immune checkpoint inhibition; alternate assignment to either:
a1 radiation followed by immune checkpoint inhibition or
a2 start with immune checkpoint inhibition alone
resulting in 2 groups of 5 patients each.

B. 10 patients with recurrent / refractory malignant lymphoma without 9p24.1
amplification who do not qualify for standard treatment; alternate assignment
to either:
b1 radiation followed by immune checkpoint inhibition or
b2 start with immune checkpoint inhibition alone
resulting in 2 groups of 5 patients each

For patients treated with combined radio-immunotherapy (groups a1 and b1),
radiation will be given prior to immune checkpoint inhibition.
Radiation (5 daily fractions of 4 Gy = 20 Gy; in 1 week) will not be given to
achieve local control, necessarily. Radiation will be given to induce
fragmentation of tumour cell components to generate neo-tumour antigens
allowing the adaptive immune system to generate a more profound and more
specific anti-tumour response.

At progression or insufficient response (in both study groups A and B),
patients will be examined whether they are eligible for (re-)introduction of
radiation followed by ICB. For patients that were assigned to the initial *no
radiotherapy arm* (groups a2 and b2) this means that radiation will be
introduced in the treatment for the first time (= delayed radio-immunotherapy).

The intervention is up-front or delayed radiation, in patients with recurrent /
refractory malignant lymphoma treated with immune checkpoint blockade.

Burden: Extra blood samples. Extra [18F]FDG PET-CT scans. Stool collection.
Optional: extra lymph node biopsy.

Risk: Checkpoint inhibitors and radiation have their own, well-known, toxicity
profiles. Combination of both therapies does not seem to lead to an excess of
toxicity. Side effects will be monitored.

Benefit: radiation may improve the effectiveness of immunotherapy in patients
with recurrent / refractory lymphoma treated with immune checkpoint blockade.

Group relatedness: Checkpoint inhibition (immune checkpoint blockade = ICB) is
standard therapy for patients with recurrent / refractory classical Hodgkin
lymphoma (cHL). Almost all these patients have amplification of 9p24.1 in their
tumour cells, harbouring amongst others the genes encoding the inhibitory PD-L1
and PD-L2 checkpoint proteins. It is very likely that all patients with 9p24.1
amplificated lymphomas (not only patients with cHL but also patients with non
Hodgkin lymphomas) will benefit from ICB therapy. Patients with recurrent /
refractory lymphoma without amplification of 9p24.1, are expected to have a
lower response rate to ICB. Radiation prior to ICB will be tested to increase
the immune response and overcome resistance.