Immunochemotherapy: Do platin-based chemotherapeutics enhance dendritic cell vaccine efficay in melanoma patients?

Melanoma is a highly malignant melanocyte-derived tumor. For patients with
resected high-risk primary melanoma and regional lymphnode metastases (stage
III), no standard systemic adjuvant treatment is available. For patients with
distant metastases (stage IV) also no standard systemic treatment is available
that has a benefit in survival. We have explored immunotherapy and have now
vaccinated well over 200 stage III and IV melanoma patients with
monocyte-derived dendritic cell (DC) vaccines and proved that DC therapy is
safe with minimal side effects. We observed that long lasting tumor specific T
cell-mediated immunological responses in ±30% of the patients is clearly linked
to highly significant (p= <0.001) increased progression free- as well as
overall- survival. It has now become obvious that cancer cells create an
immunosuppressive microenvironment paralyzing the effector arm of the immune
system. Successfully activated tumor-specific T cells encounter a large amount
of suppressive networks at the tumor site, such as suppression by regulatory T
cells, inhibitory molecules expressed by tumor cells, and a cytokine milieu
that skews the T cells into an ineffective Th2 type of response [1]. This
demonstrates that cancer vaccines will only be effective if at the same time we
succeed in reversing immunesuppression.
Cytotoxic chemotherapy and radiotherapy have long been viewed as strategies
that directly impact the viability of the tumor cell, and that the immune
system contributed little to their efficacy. The commonly held opinion was that
chemotherapy and immunotherapy could not be combined because of the
myelo-suppressive effect of most chemotherapeutic agents. However, it becomes
increasingly obvious that chemotherapy also possess the capacity to trigger
tumor antigen release and danger signals in a manner that provokes engagement
of innate and adaptive immunity that may be capitalized upon.
Small proof-of-concept clinical trials in cancer patients indicate that the
efficacy of anti-cancer vaccines may indeed be enhanced by chemotherapy [2].
Also our own preliminary observations indicate that chemotherapeutic agents, in
particular platinum compounds (cisplatin, carboplatin and oxaliplatin) are
immunogenic and may contribute to reverse tumor cell induced
immunosuppression/immune deviation.
We hypothesize that DC vaccination, when combined with other more conventional
anti-tumor treatments such as chemotherapy, that eradicate large numbers of
cancer cells, may allow the T cells to clear the remaining cancer cells and to
provide immunological memory to prevent relapse.

This is an exploratory study and the primary objective is the immunogenicity
and feasibility of combined chemotherapy-DC vaccination. The secondary
objectives are the toxicity and clinical efficacy. This study will provide
important data on the immunological efficacy of DC immunochemotherapy.

This study is an open label randomized phase II study.

Stage III and IV melanoma patients will be vaccinated three times biweekly with
mature DC injected intradermally and intravenously loaded with mRNA encoding
tumor-associated antigens gp100 and tyrosinase and pulsed with KLH as an immune
control. In arm A, each DC vaccine will be preceded by cisplatin infusion (50
mg/m2, 1-2h before DC injection). We aim to include 54 evaluable patients, 32
stage IV patients and 22 stage III patients within 2 months after radical
regional lymphnode dissection, who will be randomized 1:1 between arm A
(chemo+DC) and arm B (DC).

Based on the experience with our cytokine/PGE2-matured DC we expect that the DC
vaccine will be well tolerated. Common and expected side effects of DC
vaccination are usually mild and include flu-like symptoms and local reaction
at injection site, both not greater than CTC grade 1. In an ongoing trial, we
investigated whether oxaliplatin chemotherapy can be combined with DC
vaccination in high-risk stage II and III colon cancer patients. They received
capecitabine and oxaliplatin chemotherapy (the current standard adjuvant
treatment for colon cancer) combined with peptide-pulsed DC injections during
the 1st and 2nd chemotherapy cycles. This treatment was well tolerated with no
serious toxicity.