Shepherding Therapeutic Cancer Vaccines through Clinical Development | Page 5

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carcinoma, and metastatic colorectal cancer have all shown promise. In each of
these cases, the median survival for standard-of-care treatment is measured in
months. Thus, trials of shorter duration can suffice to show efficacy with
statistical significance measured by increasing median overall survival by
months instead of years.

Just as endpoint
selection, dosing
regimen, and trial
design are critical,
careful definition
of the patient
population that is
likely to benefit
from an
immunotherapy is
important.

Suboptimal dose and regimen. With therapeutic cancer vaccines, no

predefined conversion factor exists for extrapolating safe dosing in animals to
humans. Indeed, even trying to predict therapeutic dose or toxicity from preclinical studies is challenging with immunotherapies. There simply isn’t as clear
a dose-response mechanism in anti-cancer immunotherapies in the same way
that exists for targeted molecular therapies. In addition, innovators and
biotechnology companies often want to rush into proof-of-concept studies and
neglect thorough development of dose and regimen information. Exploring a
variety of immunotherapy doses and regimens, including the selection of an
immunological adjuvant, (e.g., BCG) or antigen generating procedure (e.g.,
tumor cryoablation), can provide critical information when planning proof-ofconcept studies, since in some cases, overdosing diminishes efficacy. By working
out optimal dosing in early phase studies the overall chances of success
increase.

Scale has its challenges. In theory, allogeneic immunotherapies are

easier to manufacture than autologous vaccines made specifically for individual
patients. However, a key drawback of allogeneic vaccines is that tumors are
distinct in their arrays of antigens. Allogeneic vaccines containing one or two
antigens may have limited efficacy in a broad patient population. In contrast,
while autologous vaccines may be more efficacious, production has proven
extremely difficult to scale from pilot-stage (pre-clinical, phase I and II) to
pivotal-stage (phase III) and from pivotal-stage to commercial scale.

Inclusion of the wrong patients. Just as endpoint selection, dosing

regimen, and trial design are critical, careful definition of the patient population
that is likely to benefit from an immunotherapy is important. Evidence seems to
suggest that extremely sick patients and those with poorly functioning immune
systems are unlikely to respond to the immunotherapy. This idea has been
borne out in post hoc analyses of several unsuccessful phase III cancer
immunotherapy trials, which showed efficacy only in the healthiest subset of
patients, those with an ECOG status of 0 or 1.

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