Download File - JOHN J. HADDAD, Ph.D.

32 Levey
anecdotal that the lives of human patients with minimal residual disease are
extended with autologous immunotherapy. It is therefore apparent that immunotherapy
in preclinical models tells us something about immunotherapy of
human cancers. Personalized cancer immunotherapy is also amenable to combination
drug treatment as a considerable body of literature demonstrates, and
the value of preclinical models of such vaccine/drug cocktails is also discussed.
Combination approaches are likely to be required for extending the application
of cancer immunotherapy beyond early-stage disease. Drugs and biologics that
slow the rate of tumor growth and/or counteract specific immune suppression
will be the key components of such combination approaches.
PREDICTIVE VALUE OF PRECLINICAL MODELS
Cancer vaccines have been extensively characterized in the preclinical setting,
providing a strong foundation and supporting rationale for studies in humans.
Several approaches are described in this section (non-exhaustive list):
l Tumor-derived heat shock protein-peptide complexes (HSPPCs)
l Tumor cells modified to secrete cytokines
l Tumor cells modified to express costimulatory B7 molecules
l Tumor cells mixed with the adjuvant bacille Calmette–Guérin (BCG)
l Lymphoma-derived immunoglobulin (idiotype)
Two key points emerge from these studies. First, therapeutic vaccination against
cancer results in benefit to the host, as measured by complete tumor rejection,
prolonged stabilization of tumor growth, and/or improved survival time. The
evidence for this point is extensive and based on a large variety of tumor models
(described below). Second, where examined, efficacy has been observed to be
greater in the minimal disease setting compared with the setting of more
advanced disease. This second point echoes the case of successful early intervention
against established smallpox infection: If smallpox vaccine is administered
within one to four days of exposure to the disease, it may prevent or lessen
the degree of illness; however, the effect of vaccination is limited if administered
once disease symptoms have already started (1,2).
Transplantable tumor lines have been used in most preclinical immunotherapy
studies, including chemically induced tumor lines and tumor lines of
spontaneous origin. As transplantable tumors tend to become selected during
passage for rapidly dividing clones that form palpable tumors within a few days
after implantation in rodents, limitations on their utility arise. The most significant
problem is the short lifespan of such tumor-bearing animals (typically
3–6 weeks) and thus the narrow window in which to administer the immunotherapeutic
and see benefit. As amplification of an immune response takes time,
the rapidly dividing tumor may outpace the development of sufficient numbers
of immune effector cells. This is a major limitation of current preclinical models.