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Page 10 of 24 Tokuyasu et al. J Cancer Metastasis Treat 2018;4:2 I http://dx.doi.org/10.20517/2394-4722.2017.52

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CTLs require CD4 help [132-135] . Indeed, adoptive cell transfer of CD4 T cells was enough to induce tumor
regression in a mouse model of melanoma [136] and in a human patient [137] .

Initial human trials
The personalized neoantigen vaccine strategy has begun to reach the clinic with the recent reports
from two Phase I trials [76,138] . These trials, on patients with advanced melanoma, demonstrate that such
[76]
therapies are safe and induce a targeted neoantigen-specific response as designed. Ott et al. enrolled
6 patients who had no evidence of disease after surgery, with 4 remaining tumor-free after 25 months.
Sahin et al. [138] enrolled 13 patients, and 8 patients remained tumor free after 23 months. The time to develop
personalized vaccines (weeks to months) remains a key obstacle, especially for patients with advanced
disease.

In an apparent pattern, both trials utilized MHC-I binding scores to select neo-epitopes (Sahin et al. [138]
combined these predictions with MHC-II binding scores). The vaccines were then seen to activate
[76]
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CD4 T cells, possibly because MHC-II binding is less restrictive [139] . In more detail, Ott et al.
selected neo-epitopes using predicted binding to HLA-A and HLA-B, and employed long peptides (15-
30 amino acids) in several pools targeting up to 20 neoantigens for five priming and two boosting
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vaccinations injected subcutaneously. They observed CD4 response almost immediately and a peak
response generally at 16 weeks, and found two to four immunogenic peptides per patient. Sahin et al. [138]
ranked mutant epitopes on a combination of predicted MHC-I and MHC-II binding, plus high expression
and variant allele frequency, and chose 10 epitopes per patient. Two synthetic RNAs were used to encode
five 27mer peptides with the single nucleotide variant (SNV) at position 14. Patients were treated with at
least eight and up to twenty neo-epitope vaccine doses injected into inguinal lymph nodes, and T cells were
developed against at least three mutations per patient, with the majority being exclusively CD4 responses.
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Neo-epitope specific CD8 T cells expanded within two to four weeks.

WHO BENEFITS?
We now return to a more general discussion of immunotherapies. The seminal studies in checkpoint
blockade therapy have primarily been done in melanoma and lung cancer. A survey of solid tumor types
that have been studied with immunotherapy, with an emphasis on understudied cancers, has been made by
Young [140] . In terms of number of clinical trials, breast cancer tops the list.

In an emerging consensus, the cancers that are best indicated for immunotherapy are slow growing,
exhibit high mutational load and low burden at the start of therapy, and are inflamed [141] . This suggests
immunotherapies may be more effective in the early stage disease setting. A correlation has been observed
in checkpoint blockade between somatic mutations per megabase and objective response rates [111] . Mutagen
induced cancers such as melanoma and lung cancer subtypes with high mutational loads were some of the
first to show durable complete response. Estimating mutational load using custom reduced gene panels [142] or
pre-existing ones [143] may aid quick assessments within the clinic. Cancer types are characterized by a wide
range of mutational loads [144] .

Recent work has sharpened focus on mismatch-repair deficiency as a biomarker to identify patients who can
benefit from PD-1 blockade, independent of tissue type [145] . The immunological phenotype of microsatellite
instability-high (MSI-H) colorectal tumors in particular may be unique [146] . In a literature review of anti-
PD-1 clinical trials, atypical responses appeared in all cancer types except tumors with mismatch-repair
deficiency and head and neck squamous cell carcinoma [147] .

While checkpoint inhibitors are often presumed to exacerbate the symptoms of patients with inflammatory/
[74]
autoimmune diseases, anecdotal reports suggest this may not be the case .