Review Article

Hapten-Induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

Table 1

Summary of the hapten-mediated tumor regression studies.

Hapten treatmentAuthor, yearHapten used for treatment, alone and in combinationTumor type/cell line used in animal and human studiesRoute of administration of haptens and hapten-modified productsObservations

Ex vivo haptenationHamaoka et al., 1979 [21]TNBS, TNP-MGG sensitization and TNP-D-GL pretreatmentX5563 cells in C3H/HeN micei.p. TNP-X5563 injectionSignificantly delayed tumor growth for up to 15 days
Fujiwara et al., 1980 [22]TNBS, TNP-MGG sensitization and TNP-D-GL pretreatmentLSTRA cells in Balb/c micei.p. TNP-X5563 injectionSignificantly delayed tumor growth for up to 10 days
Flood et al., 1987 [23]TNBS, N/AProgressor and regressor fibrosarcomas in C3H/HeN mices.c. TNP-regressor/TNP-progressor injectionSignificantly delayed tumor growth for up to 30 days
Berd et al., 1993 [30]DNFB, DNFB sensitization and CY pretreatment combined with BCG and nodal resectionStages III and IV metastatic melanoma in patients i.d. DNP-autologous melanoma injection5/46 patient responses for metastatic melanoma and 59% 2-year survival postnodal resection
Sato et al., 1995 [29]DNFB, DNFB sensitization and CY pretreatment combined with BCG and nodal resectionStages III and IV metastatic melanoma in patients i.d. DNP-autologous melanoma injectionIFNγ producing CD8 T cells that killed DNP-melanoma only
Sato et al., 1997 [27]DNFB, DNFB sensitization and CY pretreatment combined with BCG and nodal resectionStages III and IV metastatic melanoma in patients i.d. DNP-autologous melanoma injectionDNP-specific T-cells recognize only hapten-modified melanoma
Berd et al., 1997 [28]DNFB, DNFB sensitization and CY pretreatment combined with BCG and nodal resectionStage III metastatic melanoma postnodal resection in patients i.d. DNP-autologous melanoma injection5-year 45% relapse-free and 58% overall survival (62 patients)
Berd et al., 2001 [26]DNFB, DNFB sensitization and CY pretreatment combined with BCG and nodal resectionStage IV melanoma with pulmonary metastases in patientsi.d. DNP-autologous melanoma injection11/83 patients had responses to treatment, only 2 had complete response
Manne et al., 2002 [25]DNFB, DNFB sensitization and CY pretreatment combined with BCG and nodal resectionStage III metastatic melanoma postnodal resection in patients i.d. DNP-autologous melanoma injectionT-cell clones from DNP-vaccine patients with similar TCR VDJ peaks and CDR3 amino acid sequences
Sojka et al., 2002 [31]DNFB, CY pretreatment combined with BCG and nodal resection410.1 cells in Balb/c mices.c. DNP-410.1 injection40% relapse-free survival with DNP-vaccine versus 20% without DNP; CD4+, and CD8+ T cells, and IFNγ and TNFα important for survival.
Berd et al., 2004 [24]DNFB, DNFB sensitization and CY pretreatment combined with BCG and nodal resectionStage III metastatic melanoma postnodal resection in patients i.d. DNP-autologous melanoma injection5-year 44% overall survival
(214 patients)

In situ haptenationFujiwara et al., 1984 [32]TNCB, TNCB sensitization and CY pretreatmentX5563 cells in C3H/HeN miceIntratumoral injection of TNCB>50% primary tumor regression and secondary tumor resistance. Helper T-cells crucial
Fujiwara et al., 1984 [33]TNCB, TNCB sensitization and CY pretreatmentX5563 cells, MCH-1-A1 cells, and MCA-induced tumors in C3H/HeN miceIntratumoral injection of TNCB>50% primary tumor regression and secondary tumor resistance. Helper T-cells crucial

Epifocal hapten applicationKlein 1969 [34]TEIB and DNCB, N/ABCC and SCC in patientsTopical hapten application on tumorReviews various complete tumor regression cases in various different cancers and patients.
Truchetet et al., 1989 [113]DNCB, N/AMetastatic melanoma in patientsTopical DNCB application on tumor Reviews the use of DNCB to treat metastatic melanoma in the clinic and in case studies
Strobbe et al., 1997 [35]DNCB, DNCB sensitization on tumor and systemic DTICRecurrent melanoma in patientsTopical DNCB application on tumor25% complete response with combined DNCB and DTIC treatment
von Nida and Quirk, 2003 [36]DNCB, DNCB sensitizationMetastatic melanoma in patientsTopical DNCB application on tumorTumor control for 7 years in metastatic melanoma patient with DNCB application
Herrmann et al., 2004 [114]DNCB, DNCB sensitizationMerkel cell carcinoma in patientsTopical DNCB application on tumorComplete tumor regression on scalp and CD3+ T-cell and CD28+, KP-1+ Macrophage infiltration
Damian et al., 2009 [39]DPCP, DPCP sensitizationMetastatic melanoma in patientsTopical DPCP application on tumorOf 7 patients, many had slow growing tumors or tumor regression at DPCP application site
Martiniuk et al., 2010 [38]DPCP, DPCP sensitizationMetastatic melanoma in patientsTopical DPCP application on tumorRole of Th17 cells in tumor regression
Kim 2012 [40]DPCP, DPCP sensitizationMetastatic melanoma in patientsTopical DPCP application on tumorRegression of melanoma nodules for 18 weeks
Wack et al., 2001 [42]DNCB, DNCB sensitization on tumor and systemic DTICB16F17 cells in C57BL/6 miceTopical DNCB application on tumor72% primary tumor regression and reduced pulmonary metastases
Wack et al., 2002 [41]DNCB, DNCB sensitization on tumor and systemic DTICB16F17 cells in C57BL/6 miceTopical DNCB application on tumorRepeat 2001 results, CD4+ and CD8+ T cells kill B16 in vitro and release IFNγ

Lu and Low 2002 [46]Folate-FITC conjugate, BSA-FITC sensitization with adjuvant GPI-0100 and systemic IL-2 and IFNαM109 cells in Balb/c micei.v. and i.p. injection folate-FITC conjugateFITC coating of tumors. 100% overall survival after optimization with combined treatment; survive secondary challenges
Lu et al., 2005 [45]Folate-FITC conjugate, BSA-FITC sensitization with adjuvant GPI-0100 and systemic IL-2 and IFNαM109 cells in Balb/c micei.p. injection folate-FITC conjugateNK-cell induced ADCC and Macrophage opsonization; CD4+ and CD8+ T-cells important. Complete tumor regression in 35 days
Antigen-hapten administrationLu et al., 2006 [44]Folate-FITC conjugate, BSA-FITC sensitization with adjuvant GPI-0100 and systemic IL-2 and IFNαM109 cells in Balb/c micei.p. injection folate-FITC conjugatePreclinical pharmacokinetic and tissue distribution studies
Lu et al., 2007 [43]Folate-DNP conjugate, KLH-DNP sensitization with adjuvant GPI-0100 and systemic IL-2 and IFNαM109 cells in Balb/c micei.p. injection folate-DNP conjugate60% cure-rate in mice
Amato et al., 2013 [47]EC17 folate-FITC conjugate, EC90 hapten fluorescein with adjuvant GPI-0100Renal cell carcinoma in patientss.c. injection folate-FITC conjugatePhase-1 Study, 1/28 patients had partial response, 15/28 had stable disease; side effects