Active specific immunotherapy with Newcastle-diseasevirus-modified autologous tumor cells following resection of liver metastases in colorectal cancer

Abstract

A group of 23 colorectal cancer patients were treated by a new type of active specific immunotherapy (ASI) following complete surgical resection of liver metastases (RO resection). For ASI treatment we used a vaccine consisting of 1 x 10(7) autologous, irradiated (200 Gy) metastases-derived tumor cells incubated with 32 hemagglutination units (HU) of Newcastle disease virus (NDV). The adjuvant vaccine therapy was started 2 weeks after surgery and was repeated five times at 14-days intervals followed by one boost 3 months later. The delayed-type hypersensitivity (DTH) skin reactions to the vaccine were measured as well as the DTH reactions to a challenge test of 1 x 10(7) non-virus-modified autologous tumor cells from liver metastases or 1 x 10(7) autologous normal liver cells. In addition 32 HU NDV alone and a standard antigen test (Merieux test) were applied pre- and post-vaccination. The vaccination was well tolerated. In 13 of 23 patients an increasing reactivity against the vaccine was observed during the vaccination procedure. Nine patients (40%) experienced an increased DTH reactivity against autologous tumor cells following vaccination, while 17% or fewer showed an increased reactivity to Merieux test antigens, NDV, or normal liver cells. The increased antitumor response was not correlated to responsiveness to NDV alone, autologous liver cells, enzymes and culture medium used for vaccine preparation or standard antigens (Merieux test). After a follow-up of at least 18 months 61% of the vaccinated patients developed tumor recurrence in comparison to 87% of a matched control groups from the same institution that had been only surgically treated. The results of this phase II trial are encouraging and should stimulate further prospective randomized studies.

Oncolytic viral therapies

“…209,210,212 Autologous NDV oncolysate was also used in a phase II trial to treat colorectal cancer after the resection of metastatic liver lesions. 213 The oncolysate was initiated 2 weeks after surgery and administered every 2 weeks for five cycles with one booster 3 months later. Nine of 23 patients had in increase in delayed-type hypersensitivity reactions when irradiated autologous tumor cells were placed intradermally after treatment.…”

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

“…Such vaccinations started in Germany as early as 1988 and now involve several hundred patients. Promising results were obtained in adjuvant studies of operated colorectal carcinoma 20,26 and breast carcinoma. 21 For advanced disease stages, additional clinical protocols were developed for breast and ovarian carcinomas 21,27 as well as for renal carcinoma, 19 in which ATV-NDV vaccination was combined with cytokines (recombinant IL-2 and recombinant IFN-␣) and conventional treatment modalities.…”

“…Results from phase II clinical studies 19,21,26,27 suggest a benefit for certain cancer patients receiving treatment with ATV-NDV with respect to postoperative recurrence-free and overall survival. On the basis of the results obtained with bs vaccine in comparison with ATV-NDV in vitro, an augmentation of clinical effectivity is to be expected when applying second-generation bs vaccine instead of first-generation vaccine.…”

“…29 In modifying an autologous vaccine, this strategy introduces costimulatory molecules together with TAA on the same cell and thus aims at the most efficient T-cell response to costimulation. 26 TCR, TCR complex; IFN-R, type I IFN receptor; TA, tumor-associated Ag; HN, HN molecule. bsCD3 vaccine, respectively).…”

Clinical development directions in oncolytic viral therapy

“…Safety and modest evidence of activity were observed. [68][69][70][71][72][73][74][75] I.v. infusion of Newcastle virus has been well tolerated.…”