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Blocking this interaction stimulate CD8+ and NK lymphocytes and increase antibody-dependent cell-
mediated cytotoxicity (ADCC). Since Cetuximab acts mainly via an ADCC mechanism, it could be
potentiated by Monalizumab. A phase II study included 40 patients to receive weekly cetuximab combined
to monalizumab every two weeks after failur of platin. The response rate, which was the primary endpoint,
was 27.8%, or 11 out of 40 patients (compared to 13% with cetuximab alone according to historical data).
[12]
The tolerance was particularly good, making this association a promising issue . It is interesting to note
that monalizumab seems to be effective after failure of an anti-PD-1.

Another phase Ib/II study investigated the combination of danvatirsen with durvalumab among patients
with metastatic HNSCC naive of anti-PD-L1. Danvatirsen is an inhibitory antisense oligonucleotide of
STAT3 (that stimulates the immunosuppressive function of the microenvironment). Among 44 treated
patients, 23% of responses (higher than those found with durvalumab monotherapy) were found with
3 complete responses. An increase of transaminases and transient thrombocytopenia were the major
[13]
toxicities and it seems there is no additive toxicity of the two treatments .

SD101 is a TLR9 agonist stimulating the activity of dendritic cells. This later became antigen-presenting
cells to activate an anti-tumor response via T lymphocytes. A phase I/II study investigated the combination
with pembrolizumab. Patients received pembrolizumab every 3 weeks and SD-101 injected into a single
tumor site each week for 4 injections and then every 3 weeks up to 7 injections. Among the 26 patients
included, the median injections of SD-101 administered were 5. Patients experienced injection site reactions
and influenza-like illness with 28% of toxicities ≥ grade 3. The immune-induced effects of pembrolizumab
do not appear to have increased. The response rate in mITT (that is to say, among the 23 patients who had
reached at least the first tumor evaluation) was 30.4% with 7 partial responses, 3 stabilities, 10 progressions
in imaging and 3 clinical progressions before the scan. Tumor size reductions ≥ 30% were observed in
injected lesions (8/18 or 44.4%) as well as in non-injected lesions (8/14 or 57.1%). At the time of the analysis,
5 of the 7 responses were ongoing (1 to 27 weeks). Therefore, stimulation of dendritic cells seems promising
[14]
with activity in the injected site, but also at a distance, at the cost however of a significant toxicity .

Epacadostat is an oral IDO1 inhibitor (indoleamine 2,3-dioxygenase) showing good phase I and II in
combination with pembrolizumab . IDO1 is an enzyme expressed in the tumor microenvironment that
[15]
has an immunosuppressive effect by decreasing tumor infiltration by cytotoxic T lymphocytes (TILs). But
[15]
in the face of phase III failures in melanoma, development has unfortunately been halted .
Associations with tyrosine kinase inhibitors (TKIs) have also been studied in a phase Ib/II study.
Lenvatinib, a broad-spectrum TKI, has been associated with pembrolizumab in 22 progressive metastatic
patients after at least one line of chemotherapy. The 24-week response rate was 36% with a median
response time of 8.2 months, a progression-free survival (PFS) of 8.2 months, and one year progression-free
survival rate of 37%. But the toxicity is important with 91% of side effect, of which 14% of grade 4 and 18%
of patients who had to stop the treatment. The main symptoms were fatigue, loss of appetite, hypertension
and digestive disorders. Associations with other less toxic tyrosine kinase inhibitors may be considered .
[16]

Another trial associated durvalumab with an activating agonist of the immune response, MEDI6974
(Ox40 agonist antibody). The treatments were administered for a short time before surgery. An increase
and activation of cytotoxic lymphocytes within the tumor has been demonstrated. This association could
[17]
potentially be interesting .
A phase I/II study investigated dendritic cell vaccination with conventional chemotherapy in patients with
[18]
head and neck cancer . Eleven patients with relapsed or refractory disease were recruited (with HLA-A2
or HLA-A24 positive as well as WT1 expression, a tumor antigen). Mature dendritic cell (DC) loaded