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Page 6 of 9 Gauduchon et al. J Cancer Metastasis Treat 2019;5:72 I http://dx.doi.org/10.20517/2394-4722.2019.023

with WT1 peptides were injected intradermally approximately every 2-3 weeks. OK-432 (TLR-4 ligand)
was administered subcutaneously near the vaccination sites to activate the DCs. Treatment was generally
well tolerated with none of the patients with grade 2 adverse events except for hematologic adverse events
with leucocytopenia and grade 2 anemia. Non-hematologic adverse events were consistent with the classic
adverse effects of chemotherapy (discomfort, nausea, anorexia, and constipation except transient erythema
at injection sites and low-grade fever). 5 patients presented a stabilization of the disease and 6 patients a
progression of the disease. The median PFS and OS were 6.4 months and 12.1 months, respectively. But the
median duration of PFS and OS of patients with stable disease was significantly longer than that of patients
with progressive disease. The median PFS was 13.0 months vs. 2.8 months (P = 0.00136) and the median OS
was 30.3 months vs. 8.1 months (P = 0.0126). Two patients had a long-term survival of 30.3 m and 44.4 m.
Furthermore, all patients with stable disease showed improvement of WT1-specific immune responses after
vaccination in all tests performed [HLA tetramer, interferon gamma (IFNγ) ELISPOT and mobilization
CD107a] as well as an increased Th1/Th2 ratio of 1.36 times on average. Dendritic cell vaccination is
[18]
therefore an interesting research path because of its efficacy in some patients and its good tolerance .

In conclusion, many promising new immunotherapies are being developed with different mechanism of
action. Some may be used alone and other combined with CPIs or other conventional therapy.

DIFFICULTY OF ASSESSING IMMUNOTHERAPY
Evaluation of immunotherapies may be different and more difficult than conventional anti-tumor
treatments. In fact, patients treated with CPI observed phenomena of pseudo-progression (tumor response
after an initial progression) and, on the contrary, hyperprogression phenomena with a rapid and significant
increase in tumor volume.

These pseudo progression are probably due to infiltration of immune and inflammatory cells and/
or a delayed clinical response. These phenomena are relatively rare but may explain the benefit of
immunotherapy treatment beyond progression. For example, in the Checkmate 141 study, of 240 patients
randomized to receive nivolumab, 146 showed progression according to RECIST. Sixty-two of these
patients continued nivolumab and 84 discontinued treatment. Of the 60 patients who continued nivolumab
evaluable for the response, 15 (25%) had not changed their tumor burden and 15 (25%) had a reduction in
the size of the target lesion (3% of patients had responded by RECIST after progression). This attests the
interest to continue the treatment beyond the progression if the general state remains correct and in the
absence of rapid progression. Note that the expression of PDL1 does not seem to differentiate patients who
[19]
will be treated or not beyond progression .

This pseudo progression can in part explain the possible increase of efficacy of subsequent chemotherapy
after failure of anti-PD-1. Indeed a French retrospective study in 82 patients receiving chemotherapy (45%
monotherapy and 55% combination therapy) after failure of immunotherapy showed a 30% responses and a
57% disease control, higher than those usually observed in the 3rd line. Chemotherapy could also activate
the immune system by releasing tumor antigens, with check point inhibitors known to remain in the body
for a long time.

Hyperprogressions are associated with poorer survival. A French retrospective study suggested that
[20]
hyperprogression can be observed in 29% of patients treated by immunotherapy . This controversial
phenomenon could be induced by an excessive immune reaction, a paradoxical action of anti-PD-1/PD-L1
promoting tumor development, or ultimately only the natural history of advanced phase cancer.

Finally, unlike conventional chemotherapy, the occurrence of autoimmune adverse events seems to correlate
with the effectiveness of the CPIs. In an analysis of 114 patients treated with anti-PD-1: 43% exhibited