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Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.

Datta J, Berk E, Xu S, Fitzpatrick E, Rosemblit C, Lowenfeld L, Goodman N, Lewis DA, Zhang PJ, Fisher C, Roses RE, DeMichele A, Czerniecki BJ - Breast Cancer Res. (2015)

Bottom Line: Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis.After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016).In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. Jashodeep.datta@uphs.upenn.edu.

ABSTRACT

Introduction: A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C.

Methods: Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization.

Results: Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) - phenotypes, and not attributable to non-pCR patients' immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

Conclusions: Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically "fixed" and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.

No MeSH data available.


Related in: MedlinePlus

Depressed anti-human epidermal growth factor receptor 2 (anti-HER2) T-helper type-1 (Th1) immunity is restored following HER2-pulsed type 1-polarized dendritic cell (DC1) immunization. a Anti-HER2 CD4+ T cell immune reactivity profiles in four patients with non-pCR (UPCC # 26113–01 to −04) undergoing HER2-pulsed DC1 vaccination in the ongoing phase I trial NCT02061423 are demonstrated at three time points: pre-vaccination (black), 3 months post vaccination (gray), and 6 months post vaccination (white). For these time points, responses to individual HER2-derived class II peptides (x-axis; p42, p98, p328, p776, p927, p1166) are graphed, with anti-CD3/CD28 serving as positive control. Anti-HER2 Th1 repertoire and cumulative responses at these time points are listed in adjoining tables. b Anti-HER2 Th1 repertoire (mean # of reactive peptides) and cumulative response (mean total SFC/106cells) increase progressively in patients with non-pCR at the 3-month and 6-month time points. SFC spot-forming cells
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Fig6: Depressed anti-human epidermal growth factor receptor 2 (anti-HER2) T-helper type-1 (Th1) immunity is restored following HER2-pulsed type 1-polarized dendritic cell (DC1) immunization. a Anti-HER2 CD4+ T cell immune reactivity profiles in four patients with non-pCR (UPCC # 26113–01 to −04) undergoing HER2-pulsed DC1 vaccination in the ongoing phase I trial NCT02061423 are demonstrated at three time points: pre-vaccination (black), 3 months post vaccination (gray), and 6 months post vaccination (white). For these time points, responses to individual HER2-derived class II peptides (x-axis; p42, p98, p328, p776, p927, p1166) are graphed, with anti-CD3/CD28 serving as positive control. Anti-HER2 Th1 repertoire and cumulative responses at these time points are listed in adjoining tables. b Anti-HER2 Th1 repertoire (mean # of reactive peptides) and cumulative response (mean total SFC/106cells) increase progressively in patients with non-pCR at the 3-month and 6-month time points. SFC spot-forming cells

Mentions: In order to determine the impact of HER2-Th1-targeted immune interventions in high-risk non-pCR patients, four non-pCR patients (cohort G; Fig. 1) were recruited to our phase I adjuvant HER2-pulsed DC1 vaccination trial (NCT02061423); demographic and clinicopathologic characteristics of enrolled patients are detailed in Table 3. Subjects received six weekly injections followed by three booster doses at three-month intervals. Vaccination-induced anti-HER2 Th1 responses were followed prospectively; Th1 reactivity in individual patients pre-vaccination and post-vaccination is illustrated in Fig. 6a. In vaccinated subjects, evaluable anti-HER2 Th1 responses measured 6 months post-vaccination (i.e., prior to the third booster) indicated significantly improved anti-HER2 Th1 repertoire (3.7 ± 0.5 post-vaccination vs 0.5 ± 0.5 pre-vaccination, p = 0.014) and cumulative response (192.3 ± 16.4 vs. 33.9 ± 19.4 SFC/106, p = 0.014) compared with pre-vaccination levels (Fig. 6b). Vaccinations were well-tolerated, with only two cases of grade-1 toxicity observed.Table 3


Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.

Datta J, Berk E, Xu S, Fitzpatrick E, Rosemblit C, Lowenfeld L, Goodman N, Lewis DA, Zhang PJ, Fisher C, Roses RE, DeMichele A, Czerniecki BJ - Breast Cancer Res. (2015)

Depressed anti-human epidermal growth factor receptor 2 (anti-HER2) T-helper type-1 (Th1) immunity is restored following HER2-pulsed type 1-polarized dendritic cell (DC1) immunization. a Anti-HER2 CD4+ T cell immune reactivity profiles in four patients with non-pCR (UPCC # 26113–01 to −04) undergoing HER2-pulsed DC1 vaccination in the ongoing phase I trial NCT02061423 are demonstrated at three time points: pre-vaccination (black), 3 months post vaccination (gray), and 6 months post vaccination (white). For these time points, responses to individual HER2-derived class II peptides (x-axis; p42, p98, p328, p776, p927, p1166) are graphed, with anti-CD3/CD28 serving as positive control. Anti-HER2 Th1 repertoire and cumulative responses at these time points are listed in adjoining tables. b Anti-HER2 Th1 repertoire (mean # of reactive peptides) and cumulative response (mean total SFC/106cells) increase progressively in patients with non-pCR at the 3-month and 6-month time points. SFC spot-forming cells
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Fig6: Depressed anti-human epidermal growth factor receptor 2 (anti-HER2) T-helper type-1 (Th1) immunity is restored following HER2-pulsed type 1-polarized dendritic cell (DC1) immunization. a Anti-HER2 CD4+ T cell immune reactivity profiles in four patients with non-pCR (UPCC # 26113–01 to −04) undergoing HER2-pulsed DC1 vaccination in the ongoing phase I trial NCT02061423 are demonstrated at three time points: pre-vaccination (black), 3 months post vaccination (gray), and 6 months post vaccination (white). For these time points, responses to individual HER2-derived class II peptides (x-axis; p42, p98, p328, p776, p927, p1166) are graphed, with anti-CD3/CD28 serving as positive control. Anti-HER2 Th1 repertoire and cumulative responses at these time points are listed in adjoining tables. b Anti-HER2 Th1 repertoire (mean # of reactive peptides) and cumulative response (mean total SFC/106cells) increase progressively in patients with non-pCR at the 3-month and 6-month time points. SFC spot-forming cells
Mentions: In order to determine the impact of HER2-Th1-targeted immune interventions in high-risk non-pCR patients, four non-pCR patients (cohort G; Fig. 1) were recruited to our phase I adjuvant HER2-pulsed DC1 vaccination trial (NCT02061423); demographic and clinicopathologic characteristics of enrolled patients are detailed in Table 3. Subjects received six weekly injections followed by three booster doses at three-month intervals. Vaccination-induced anti-HER2 Th1 responses were followed prospectively; Th1 reactivity in individual patients pre-vaccination and post-vaccination is illustrated in Fig. 6a. In vaccinated subjects, evaluable anti-HER2 Th1 responses measured 6 months post-vaccination (i.e., prior to the third booster) indicated significantly improved anti-HER2 Th1 repertoire (3.7 ± 0.5 post-vaccination vs 0.5 ± 0.5 pre-vaccination, p = 0.014) and cumulative response (192.3 ± 16.4 vs. 33.9 ± 19.4 SFC/106, p = 0.014) compared with pre-vaccination levels (Fig. 6b). Vaccinations were well-tolerated, with only two cases of grade-1 toxicity observed.Table 3

Bottom Line: Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis.After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016).In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. Jashodeep.datta@uphs.upenn.edu.

ABSTRACT

Introduction: A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C.

Methods: Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization.

Results: Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) - phenotypes, and not attributable to non-pCR patients' immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

Conclusions: Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically "fixed" and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.

No MeSH data available.


Related in: MedlinePlus