Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

Abstract

Key words: melanoma; vaccine; immunotherapy; autologous; cyclophosphamideStudies performed and published over the past 30 years have made it clear that immunizing a tumor-bearing patient to his or her own tumor cells is exceedingly difficult. An appealing explanation for this difficulty is that tumor antigens are weakly immunogenic and often induce tolerance, i.e., paralysis of the immune response, rather than effective immunity. 1 Fortunately, advances in basic immunology have disclosed a number of ways of breaking immunologic tolerance. One way is the judicious use of cytotoxic drugs. In 1967, Maguire and Ettore 2 made the surprising discovery that administration of cyclophosphamide to animals prior to an immunization caused the cell-mediated immune response to be augmented rather than suppressed. We have shown that this phenomenon applies to cancer-bearing humans as well. Thus, the administration of low-dose (300 mg/m 2 ) cyclophosphamide prior to an immunization with autologous tumor cells greatly increased the development of cell-mediated immunity to those cells. 3 A second approach to circumventing tolerance is the use of haptens-small molecules that are incapable of inducing an immune response unless they are coupled to a larger molecule. Coupling of a hapten to a protein, i.e., hapten modification, often results in the induction of an immune response to the protein that would otherwise not be possible. For example, Weigle, 4 in a series of now classic experiments, immunized mice with hapten-modified thyroglobulin. This resulted in the induction of an immune response not only to the hapten-modified thyroglobulin, but also to unmodified, i.e., native, thyroglobulin and produced autoimmune thyroiditis. A similar phenomenon was observed more recently by Neurath et al. 5 They found that application of the hapten dinitrophenyl to the colonic mucosa of mice resulted in the development of an autoimmune colitis, similar to human ulcerative colitis. Initially, these mice developed cellular immunity to the haptenmodified mucosa. However, as the chemically modified mucosa cells were shed, a potent immune response to the normal, unmodified mucosa developed, which led to the autoimmune pathology.The immunologic basis of these interesting phenomena is now clear: there are T lymphocytes generated by immunization with hapten-modified cells that are reactive to both modified and unmodified cells. For example, class I MHC-restricted T-cell clones generated from mice immunized with TNP-modified syngeneic lymphocytes respond to MHC-associated, TNP-modified "self" peptides. Furthermore, some TNP-reactive clones respond to certain MHC-binding, unmodified peptides as well. 6 These observations in animal models provide a strong rationale for a human cancer vaccine consisting of autologous tumor cells modified with a hapten, DNP, preceded by the administration of low-dose cyclophosphamide. We have observed that administration of DNP vaccine to patients with metastatic melanoma induces a unique reaction-the development of inflamma...

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma

“…In a previous study, we found a significant correlation between the development of strong positive DTH and (Lotem et al, 2002). Similar findings were reported by Berd et al (1990Berd et al ( , 2001 and Baars et al (2000). The results presented here suggest that this is not only a prognostic marker but may also be a prerequisite for tumour regression, attesting to the presence of tumour-specific T cells.…”

“…The increased susceptibility of skin and lung metastases to immunotherapy has been addressed before (Berd et al, 2001;Hsueh et al, 1999). Interestingly, several of our responding patients had received cytodestructive modality previously: ILP or radiotherapy, to which they responded by transient initial response.…”

TCR Rearrangement in Lymphocytes Infiltrating Melanoma Metastases After Administration of Autologous Dinitrophenyl-Modified Vaccine

“…Our group has been conducting clinical trials of a human cancer vaccine consisting of autologous tumor cells modified with the hapten, dinitrophenyl (DNP) 3 (12)(13)(14). The rationale for this approach is the well-established observation that immunization with a hapten-modified protein can induce an immune response to the unmodified, natural protein even when that protein is a normal self-Ag.…”

Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications

“…In addition, typical examples of late curve divergence that agree with the delayed action-late benefit model can be derived from studies of melanoma and prostatic cancer [4,2,3]. However, although a delayed clinical efficacy was observed in these studies, cellular responses have commonly been detected within weeks after vaccination, suggesting that the time to mount an immune response does not fully explain the delayed efficacy [15,18]. Furthermore, the finding, in one study [8], that a marked delayed separation of survival curves may occur more than 3 years after end of therapy makes it unlikely that late development of immune response can be the only factor responsible for delayed separation of survival curves in immunotherapy trials.…”

“…Delayed action -late benefit model Earlier discussions of the reason for delayed separation of survival curves in immunotherapy trials have focused on the fact that the development of a clinically effective immune response may take time and that, therefore, the benefit of the treatment will not be evident until late, sometimes only after several months of treatment [9]. This model gains some support from patients with metastatic disease undergoing immunotherapy, who initially display progression but then later respond to therapy [15][16][17]. In addition, typical examples of late curve divergence that agree with the delayed action-late benefit model can be derived from studies of melanoma and prostatic cancer [4,2,3].…”