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Pre-immature dendritic cells (PIDC) pulsed with HPV16 E6 or E7 peptide are capable of eliciting specific immune response in patients with advanced cervical cancer.

Rahma OE, Herrin VE, Ibrahim RA, Toubaji A, Bernstein S, Dakheel O, Steinberg SM, Abu Eid R, Mkrtichyan M, Berzofsky JA, Khleif SN - J Transl Med (2014)

Bottom Line: HPV16 E6 was found to be homologous to HPV18 E6 in both vivo and vitro.There were no RECIST responses in any patient.The majority of toxicities were grade I and II.

View Article: PubMed Central - PubMed

Affiliation: Cancer Vaccine Branch, CCR, NCI, 10 Center Drive, Bethesda 20892, MD, USA. skhleif@gru.edu.

ABSTRACT

Background: The protein products of the early genes E6 and E7 in high-risk HPV types 16 and 18 have been implicated in the oncogenic capability of these viruses. Therefore, these peptides represent attractive vaccine therapy targets.

Methods: Thirty-two patients with advanced cervical cancer (HPV16 or 18 positive) were treated with HPV16 E6 (18-26) (Arm A) or HPV16 E7 (12-20) peptide (Arm B) pulsed on PBMCs in order to illicit immune response against the relevant peptide on both arms. These PBMCs were cultured for a short time (48 hours only) and in the presence of GM- CSF, accordingly, they were identified as "Pre-Immature Dentritic Cells".

Results: 51Cr release assay and ELISPOT demonstrated evidence of specific immune response against the relevant peptide in 10/16 (63%) evaluable patients in arm A and 7/12 (58%) in arm B. HPV16 E6 was found to be homologous to HPV18 E6 in both vivo and vitro. The median overall survival (OS) and progression free survival (PFS) for the full cohort was 10.0 and 3.5 months, respectively. There were no RECIST responses in any patient. The majority of toxicities were grade I and II.

Conclusions: We demonstrated the feasibility and ability of Pre-Immature Dentritic Cells pulsed with HPV16 E6 (18-26) or HPV16 E7 (12-20) to induce a specific immune response against the relevant peptide despite the advanced disease of the cervical cancer patients treated on this trial. We believe that this observation deserves further investigations.

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The cytolytic activity of patient 6A’ PBMCs post one vaccination. Cervical cancer cell lines were used as target cells. Caski (HPV16 positive, HLA-A2 cell line) closed squares; CAV (HPV 18 high and HLA-A2 cell line), open circles; MS751 (an HPV 18 low, HLA-A2 cell line), open diamonds; ME180 (HPV negative, HLA-A2 negative cervical cancer cell line), open triangles. Highest percentage of specific lysis was seen with the Caski and Cav cell lines, followed by the MS751 and only background level lysis was seen when the ME180 cell line was used as a target.
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Fig2: The cytolytic activity of patient 6A’ PBMCs post one vaccination. Cervical cancer cell lines were used as target cells. Caski (HPV16 positive, HLA-A2 cell line) closed squares; CAV (HPV 18 high and HLA-A2 cell line), open circles; MS751 (an HPV 18 low, HLA-A2 cell line), open diamonds; ME180 (HPV negative, HLA-A2 negative cervical cancer cell line), open triangles. Highest percentage of specific lysis was seen with the Caski and Cav cell lines, followed by the MS751 and only background level lysis was seen when the ME180 cell line was used as a target.

Mentions: To test whether E6 protein is processed and presented in the proper context of MHC class I and to test the ability of T-cells generated by HPV16 E6 to cross react with an internally processed HPV18 E6, we tested the ability of post vaccination PBMCs to lyse established HLA-A2 positive cervical cancer cell lines harboring either the HPV16 or HPV18 genome. We found that these primed T-cells were able to lyse Caski cells (HLA-A2 and HPV16 positive), Cav cell line (HLA-A2 with a high number of copies of HPV18) and, to a lesser extent, the MS751 cell line (HLA-A2 harboring lower number of copies of HPV18) but not the HLA-A2 and HPV negative cervical cancer cells (ME180). We were able to see specific lysis in those cell lines and the lysis was higher in cell lines that carry higher number of copies of HPV (Figure 2). Similarly, the effector cells generated through the E7 vaccine were tested against tumor cells either expressing the HPV16 E7 genome or HPV16 E7 negative cell line. We were able to detect lysis of the E7 positive cell lines and not the E7 negative ones. Furthermore, effector cells were able to lyse only the HLA-A2 positive cell lines and not the HLA-A2 negative ones (data not shown).Figure 2


Pre-immature dendritic cells (PIDC) pulsed with HPV16 E6 or E7 peptide are capable of eliciting specific immune response in patients with advanced cervical cancer.

Rahma OE, Herrin VE, Ibrahim RA, Toubaji A, Bernstein S, Dakheel O, Steinberg SM, Abu Eid R, Mkrtichyan M, Berzofsky JA, Khleif SN - J Transl Med (2014)

The cytolytic activity of patient 6A’ PBMCs post one vaccination. Cervical cancer cell lines were used as target cells. Caski (HPV16 positive, HLA-A2 cell line) closed squares; CAV (HPV 18 high and HLA-A2 cell line), open circles; MS751 (an HPV 18 low, HLA-A2 cell line), open diamonds; ME180 (HPV negative, HLA-A2 negative cervical cancer cell line), open triangles. Highest percentage of specific lysis was seen with the Caski and Cav cell lines, followed by the MS751 and only background level lysis was seen when the ME180 cell line was used as a target.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4269078&req=5

Fig2: The cytolytic activity of patient 6A’ PBMCs post one vaccination. Cervical cancer cell lines were used as target cells. Caski (HPV16 positive, HLA-A2 cell line) closed squares; CAV (HPV 18 high and HLA-A2 cell line), open circles; MS751 (an HPV 18 low, HLA-A2 cell line), open diamonds; ME180 (HPV negative, HLA-A2 negative cervical cancer cell line), open triangles. Highest percentage of specific lysis was seen with the Caski and Cav cell lines, followed by the MS751 and only background level lysis was seen when the ME180 cell line was used as a target.
Mentions: To test whether E6 protein is processed and presented in the proper context of MHC class I and to test the ability of T-cells generated by HPV16 E6 to cross react with an internally processed HPV18 E6, we tested the ability of post vaccination PBMCs to lyse established HLA-A2 positive cervical cancer cell lines harboring either the HPV16 or HPV18 genome. We found that these primed T-cells were able to lyse Caski cells (HLA-A2 and HPV16 positive), Cav cell line (HLA-A2 with a high number of copies of HPV18) and, to a lesser extent, the MS751 cell line (HLA-A2 harboring lower number of copies of HPV18) but not the HLA-A2 and HPV negative cervical cancer cells (ME180). We were able to see specific lysis in those cell lines and the lysis was higher in cell lines that carry higher number of copies of HPV (Figure 2). Similarly, the effector cells generated through the E7 vaccine were tested against tumor cells either expressing the HPV16 E7 genome or HPV16 E7 negative cell line. We were able to detect lysis of the E7 positive cell lines and not the E7 negative ones. Furthermore, effector cells were able to lyse only the HLA-A2 positive cell lines and not the HLA-A2 negative ones (data not shown).Figure 2

Bottom Line: HPV16 E6 was found to be homologous to HPV18 E6 in both vivo and vitro.There were no RECIST responses in any patient.The majority of toxicities were grade I and II.

View Article: PubMed Central - PubMed

Affiliation: Cancer Vaccine Branch, CCR, NCI, 10 Center Drive, Bethesda 20892, MD, USA. skhleif@gru.edu.

ABSTRACT

Background: The protein products of the early genes E6 and E7 in high-risk HPV types 16 and 18 have been implicated in the oncogenic capability of these viruses. Therefore, these peptides represent attractive vaccine therapy targets.

Methods: Thirty-two patients with advanced cervical cancer (HPV16 or 18 positive) were treated with HPV16 E6 (18-26) (Arm A) or HPV16 E7 (12-20) peptide (Arm B) pulsed on PBMCs in order to illicit immune response against the relevant peptide on both arms. These PBMCs were cultured for a short time (48 hours only) and in the presence of GM- CSF, accordingly, they were identified as "Pre-Immature Dentritic Cells".

Results: 51Cr release assay and ELISPOT demonstrated evidence of specific immune response against the relevant peptide in 10/16 (63%) evaluable patients in arm A and 7/12 (58%) in arm B. HPV16 E6 was found to be homologous to HPV18 E6 in both vivo and vitro. The median overall survival (OS) and progression free survival (PFS) for the full cohort was 10.0 and 3.5 months, respectively. There were no RECIST responses in any patient. The majority of toxicities were grade I and II.

Conclusions: We demonstrated the feasibility and ability of Pre-Immature Dentritic Cells pulsed with HPV16 E6 (18-26) or HPV16 E7 (12-20) to induce a specific immune response against the relevant peptide despite the advanced disease of the cervical cancer patients treated on this trial. We believe that this observation deserves further investigations.

Show MeSH
Related in: MedlinePlus