TBD Meeting (5324-16)

 

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

122154_Annels_Nicola_UK_web.jpg

“Whilst the use of BCG [Bacille Calmette-Guerin] as an immunotherapy for non-muscle invasive bladder cancer has significantly improved disease-specific survival, the potential for serious side effects and local and systemic toxicity, together with the fact that there is a significant proportion of non-responding patients to BCG, highlights the need to develop future immune-based therapies to overcome these problems,” she said at the annual meeting of the Society for Immunotherapy of Cancer.

CVA21 is a proprietary formulation of coxsackievirus A21, a common cold virus. It targets intracellular adhesion molecule-1 (ICAM-1), and has been shown to have potent oncolytic activity against both non-muscle invasive bladder cancer (NMIBC) cell lines and ex vivo human bladder tumors. Delivering CVA21 with low-dose mitomycin C has been shown to enhance viral replication by increasing cell surface expression levels of ICAM-1, Dr. Annels noted.

In the stage I/II CANON study, the investigators studied the tolerability and safety of escalating doses of CVA21 alone or in combination with 10 mg mitomycin C in 16 patients with untreated NMIBC who were scheduled to undergo transurethral resection of bladder tumor (TURBT).

On serial cystoscopic photographs, the investigators saw evidence of anticancer activity including one complete response in one of three patients on CVA21 monotherapy at the highest of three doses, as well as virally-induced tumor inflammation.

Additional evidence of viral tumor targeting came from detection of secondary viral-load peaks in urine, and immunohistochemical analysis of tissues excised during TURBT, which tissue displayed tumor-specific viral replication and programmed cell death.

The authors also found that tissues treated with CVA21 showed upregulation of both interferon-response genes and immune checkpoint inhibitory genes compared with tissues from historical controls. This finding suggests that the antitumor effect of CVA21 might be enhanced by sequential administration of the virus followed by an immune checkpoint inhibitor, Dr. Annels said.

Patients tolerated the administration of CVA21 well, and there were no product-related adverse events greater than grade 1.

The activity observed thus “is likely to provide a strong signal in generating both a strong local and systemic anti-tumor response,” she said.

The study was funded by The Prostate Project, RingRose Foundation, Prostate Cancer UK, Topic of Cancer UK, Breast Cancer Campaign, the European Union, and Viralytics. Dr. Annels reported no conflicts of interest.

 

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

122154_Annels_Nicola_UK_web.jpg

“Whilst the use of BCG [Bacille Calmette-Guerin] as an immunotherapy for non-muscle invasive bladder cancer has significantly improved disease-specific survival, the potential for serious side effects and local and systemic toxicity, together with the fact that there is a significant proportion of non-responding patients to BCG, highlights the need to develop future immune-based therapies to overcome these problems,” she said at the annual meeting of the Society for Immunotherapy of Cancer.

CVA21 is a proprietary formulation of coxsackievirus A21, a common cold virus. It targets intracellular adhesion molecule-1 (ICAM-1), and has been shown to have potent oncolytic activity against both non-muscle invasive bladder cancer (NMIBC) cell lines and ex vivo human bladder tumors. Delivering CVA21 with low-dose mitomycin C has been shown to enhance viral replication by increasing cell surface expression levels of ICAM-1, Dr. Annels noted.

In the stage I/II CANON study, the investigators studied the tolerability and safety of escalating doses of CVA21 alone or in combination with 10 mg mitomycin C in 16 patients with untreated NMIBC who were scheduled to undergo transurethral resection of bladder tumor (TURBT).

On serial cystoscopic photographs, the investigators saw evidence of anticancer activity including one complete response in one of three patients on CVA21 monotherapy at the highest of three doses, as well as virally-induced tumor inflammation.

Additional evidence of viral tumor targeting came from detection of secondary viral-load peaks in urine, and immunohistochemical analysis of tissues excised during TURBT, which tissue displayed tumor-specific viral replication and programmed cell death.

The authors also found that tissues treated with CVA21 showed upregulation of both interferon-response genes and immune checkpoint inhibitory genes compared with tissues from historical controls. This finding suggests that the antitumor effect of CVA21 might be enhanced by sequential administration of the virus followed by an immune checkpoint inhibitor, Dr. Annels said.

Patients tolerated the administration of CVA21 well, and there were no product-related adverse events greater than grade 1.

The activity observed thus “is likely to provide a strong signal in generating both a strong local and systemic anti-tumor response,” she said.

The study was funded by The Prostate Project, RingRose Foundation, Prostate Cancer UK, Topic of Cancer UK, Breast Cancer Campaign, the European Union, and Viralytics. Dr. Annels reported no conflicts of interest.

 

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

122154_Annels_Nicola_UK_web.jpg

“Whilst the use of BCG [Bacille Calmette-Guerin] as an immunotherapy for non-muscle invasive bladder cancer has significantly improved disease-specific survival, the potential for serious side effects and local and systemic toxicity, together with the fact that there is a significant proportion of non-responding patients to BCG, highlights the need to develop future immune-based therapies to overcome these problems,” she said at the annual meeting of the Society for Immunotherapy of Cancer.

CVA21 is a proprietary formulation of coxsackievirus A21, a common cold virus. It targets intracellular adhesion molecule-1 (ICAM-1), and has been shown to have potent oncolytic activity against both non-muscle invasive bladder cancer (NMIBC) cell lines and ex vivo human bladder tumors. Delivering CVA21 with low-dose mitomycin C has been shown to enhance viral replication by increasing cell surface expression levels of ICAM-1, Dr. Annels noted.

In the stage I/II CANON study, the investigators studied the tolerability and safety of escalating doses of CVA21 alone or in combination with 10 mg mitomycin C in 16 patients with untreated NMIBC who were scheduled to undergo transurethral resection of bladder tumor (TURBT).

On serial cystoscopic photographs, the investigators saw evidence of anticancer activity including one complete response in one of three patients on CVA21 monotherapy at the highest of three doses, as well as virally-induced tumor inflammation.

Additional evidence of viral tumor targeting came from detection of secondary viral-load peaks in urine, and immunohistochemical analysis of tissues excised during TURBT, which tissue displayed tumor-specific viral replication and programmed cell death.

The authors also found that tissues treated with CVA21 showed upregulation of both interferon-response genes and immune checkpoint inhibitory genes compared with tissues from historical controls. This finding suggests that the antitumor effect of CVA21 might be enhanced by sequential administration of the virus followed by an immune checkpoint inhibitor, Dr. Annels said.

Patients tolerated the administration of CVA21 well, and there were no product-related adverse events greater than grade 1.

The activity observed thus “is likely to provide a strong signal in generating both a strong local and systemic anti-tumor response,” she said.

The study was funded by The Prostate Project, RingRose Foundation, Prostate Cancer UK, Topic of Cancer UK, Breast Cancer Campaign, the European Union, and Viralytics. Dr. Annels reported no conflicts of interest.

 

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

122142_McNeel_Douglas_web.jpg

Dr. McNeel and colleagues are exploring the therapeutic potential of combining the PD-1 inhibitor pembrolizumab (Keytruda) with an investigational DNA vaccine targeted against prostatic acid phosphatase (PAP), the same antigen targeted by sipuleucel-T (Provenge).

They presented data in a scientific poster from a pilot study of the combination in patients with metastatic, castration-resistant prostate cancer (mCRPC).

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

 

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

122142_McNeel_Douglas_web.jpg

Dr. McNeel and colleagues are exploring the therapeutic potential of combining the PD-1 inhibitor pembrolizumab (Keytruda) with an investigational DNA vaccine targeted against prostatic acid phosphatase (PAP), the same antigen targeted by sipuleucel-T (Provenge).

They presented data in a scientific poster from a pilot study of the combination in patients with metastatic, castration-resistant prostate cancer (mCRPC).

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

 

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

122142_McNeel_Douglas_web.jpg

Dr. McNeel and colleagues are exploring the therapeutic potential of combining the PD-1 inhibitor pembrolizumab (Keytruda) with an investigational DNA vaccine targeted against prostatic acid phosphatase (PAP), the same antigen targeted by sipuleucel-T (Provenge).

They presented data in a scientific poster from a pilot study of the combination in patients with metastatic, castration-resistant prostate cancer (mCRPC).

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

121966_Tsai_Katy_SanDiego_web.jpg

The reasons for the difference are not known. Possibly, sex hormones or factors unique to women, such as variations in populations of T-regulatory cells (T-regs) as a result of pregnancy, may be implicated, Dr. Tsai said in an interview.

“There has been a lot of interesting data coming out recently about the influence of sex hormones on the immune regulatory response in general, so I do think that is something that needs to be explored further,” Dr. Tsai said at the annual meeting of the Society for Immunotherapy of Cancer.

“There are some interesting data to suggest that perhaps women, and in particular pregnant women or perhaps even women who have higher parity than those who are nulliparous, may have higher circulating levels of T-regs that may contribute to dampening this immune response,” she said.

Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

121966_Tsai_Katy_SanDiego_web.jpg

The reasons for the difference are not known. Possibly, sex hormones or factors unique to women, such as variations in populations of T-regulatory cells (T-regs) as a result of pregnancy, may be implicated, Dr. Tsai said in an interview.

“There has been a lot of interesting data coming out recently about the influence of sex hormones on the immune regulatory response in general, so I do think that is something that needs to be explored further,” Dr. Tsai said at the annual meeting of the Society for Immunotherapy of Cancer.

“There are some interesting data to suggest that perhaps women, and in particular pregnant women or perhaps even women who have higher parity than those who are nulliparous, may have higher circulating levels of T-regs that may contribute to dampening this immune response,” she said.

Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

121966_Tsai_Katy_SanDiego_web.jpg

The reasons for the difference are not known. Possibly, sex hormones or factors unique to women, such as variations in populations of T-regulatory cells (T-regs) as a result of pregnancy, may be implicated, Dr. Tsai said in an interview.

“There has been a lot of interesting data coming out recently about the influence of sex hormones on the immune regulatory response in general, so I do think that is something that needs to be explored further,” Dr. Tsai said at the annual meeting of the Society for Immunotherapy of Cancer.

“There are some interesting data to suggest that perhaps women, and in particular pregnant women or perhaps even women who have higher parity than those who are nulliparous, may have higher circulating levels of T-regs that may contribute to dampening this immune response,” she said.

Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

NATIONAL HARBOR, MD. – Density in tumors of two key immune cells may be a biomarker for response to an inhibitor of programmed death–ligand 1 (PD-L1) among patients with non–small cell lung cancer (NSCLC).

Patients with NSCLC whose tumors bore high densities of both CD8-positive cytotoxic T lymphocytes and PD-L1 had significantly better outcomes when treated with the investigational PD-L1 inhibitor durvalumab than patients with high densities of either cell type alone, reported Sonja Althammer, PhD, a scientist at Definiens AG, maker of the anti–PD-L1 compound.

Althammer_Sonja_web.jpg

“We were looking at the predictive character of PD-L1 and CD8, and interestingly, we found out that it is a combination of the two that best predicts the response to durvalumab of the patients,” she said at the Society for Immunotherapy of Cancer annual meeting.

Dr. Althammer and her colleagues assessed the use of an automated image analysis and pattern recognition system to determine whether tumor-infiltrating CD8-positive cytotoxic T lymphocytes and PD-L1 densities could identify patients most likely to respond to the investigational PD-L1 inhibitor durvalumab.

“The hypothesis that we had in mind was that the interaction between both cell populations is important, so both cell populations should be present,” she said.

The investigators analyzed archived or fresh tumor biopsy samples from 163 patients with untreated or previously treated NSCLC (median 3 prior lines of therapy) who were enrolled in a nonrandomized phase I/II trial evaluating durvalumab in advanced NSCLC and other solid tumors.

They matched CD8 and PD-L1 immunohistochemistry-stained sections from tissues blocks. High PD-L1 expression was defined as a 25% or higher proportion of PD-L1–positive tumor cells with membrane staining at any intensity.

The images were then evaluated with an automated system, with results matched to clinical outcomes based on the densities of CD8-positive and PD-L1–positive cells, and PD-L1 alone from pre-treatment biopsy samples using a discovery set (84 samples) and validation set (79). The datasets were matched on baseline PD-L1 status, histology, Eastern Cooperative Oncology Group performance status, lines of therapy, and response.

In a training set looking at overall response rate (ORR), they found evidence to suggest that the combination of CD8 and PD-L1 positivity was associated with a higher ORR: 42%, compared with 31% for CD8-positive expression alone, 27% for PD-L1–positive alone, and 7% for CD8-positive PD-L1–negative (less than 25% expression) alone.

They then examined the predictive ability of the combined markers, and found that over approximately 28 months of follow-up, patients with CD8-positive and PD-L1–positive dense tumors had better overall survival (median overall survival, 24.3 months), compared with PD-L1–positive only patients (median overall survival, 17.1 months), CD8-positive only patients (median overall survival, 17.8 months), or the entire patient sample (median overall survival, 11.1 months).

Similarly, progression-free survival was also better among patients with high expression of both markers (respective median progression-free survival was 7.3, 3.6, 5.3, and 2.8 months).

Dr. Althammer acknowledged that the findings were preliminary and needed to be confirmed independently in larger studies.

The study was supported by MedImmune. Sonja Althammer is an employee of Definiens AG, which is a subsidiary of MedImmune/AstraZeneca.

NATIONAL HARBOR, MD. – Density in tumors of two key immune cells may be a biomarker for response to an inhibitor of programmed death–ligand 1 (PD-L1) among patients with non–small cell lung cancer (NSCLC).

Patients with NSCLC whose tumors bore high densities of both CD8-positive cytotoxic T lymphocytes and PD-L1 had significantly better outcomes when treated with the investigational PD-L1 inhibitor durvalumab than patients with high densities of either cell type alone, reported Sonja Althammer, PhD, a scientist at Definiens AG, maker of the anti–PD-L1 compound.

Althammer_Sonja_web.jpg

“We were looking at the predictive character of PD-L1 and CD8, and interestingly, we found out that it is a combination of the two that best predicts the response to durvalumab of the patients,” she said at the Society for Immunotherapy of Cancer annual meeting.

Dr. Althammer and her colleagues assessed the use of an automated image analysis and pattern recognition system to determine whether tumor-infiltrating CD8-positive cytotoxic T lymphocytes and PD-L1 densities could identify patients most likely to respond to the investigational PD-L1 inhibitor durvalumab.

“The hypothesis that we had in mind was that the interaction between both cell populations is important, so both cell populations should be present,” she said.

The investigators analyzed archived or fresh tumor biopsy samples from 163 patients with untreated or previously treated NSCLC (median 3 prior lines of therapy) who were enrolled in a nonrandomized phase I/II trial evaluating durvalumab in advanced NSCLC and other solid tumors.

They matched CD8 and PD-L1 immunohistochemistry-stained sections from tissues blocks. High PD-L1 expression was defined as a 25% or higher proportion of PD-L1–positive tumor cells with membrane staining at any intensity.

The images were then evaluated with an automated system, with results matched to clinical outcomes based on the densities of CD8-positive and PD-L1–positive cells, and PD-L1 alone from pre-treatment biopsy samples using a discovery set (84 samples) and validation set (79). The datasets were matched on baseline PD-L1 status, histology, Eastern Cooperative Oncology Group performance status, lines of therapy, and response.

In a training set looking at overall response rate (ORR), they found evidence to suggest that the combination of CD8 and PD-L1 positivity was associated with a higher ORR: 42%, compared with 31% for CD8-positive expression alone, 27% for PD-L1–positive alone, and 7% for CD8-positive PD-L1–negative (less than 25% expression) alone.

They then examined the predictive ability of the combined markers, and found that over approximately 28 months of follow-up, patients with CD8-positive and PD-L1–positive dense tumors had better overall survival (median overall survival, 24.3 months), compared with PD-L1–positive only patients (median overall survival, 17.1 months), CD8-positive only patients (median overall survival, 17.8 months), or the entire patient sample (median overall survival, 11.1 months).

Similarly, progression-free survival was also better among patients with high expression of both markers (respective median progression-free survival was 7.3, 3.6, 5.3, and 2.8 months).

Dr. Althammer acknowledged that the findings were preliminary and needed to be confirmed independently in larger studies.

The study was supported by MedImmune. Sonja Althammer is an employee of Definiens AG, which is a subsidiary of MedImmune/AstraZeneca.

NATIONAL HARBOR, MD. – Density in tumors of two key immune cells may be a biomarker for response to an inhibitor of programmed death–ligand 1 (PD-L1) among patients with non–small cell lung cancer (NSCLC).

Patients with NSCLC whose tumors bore high densities of both CD8-positive cytotoxic T lymphocytes and PD-L1 had significantly better outcomes when treated with the investigational PD-L1 inhibitor durvalumab than patients with high densities of either cell type alone, reported Sonja Althammer, PhD, a scientist at Definiens AG, maker of the anti–PD-L1 compound.

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“We were looking at the predictive character of PD-L1 and CD8, and interestingly, we found out that it is a combination of the two that best predicts the response to durvalumab of the patients,” she said at the Society for Immunotherapy of Cancer annual meeting.

Dr. Althammer and her colleagues assessed the use of an automated image analysis and pattern recognition system to determine whether tumor-infiltrating CD8-positive cytotoxic T lymphocytes and PD-L1 densities could identify patients most likely to respond to the investigational PD-L1 inhibitor durvalumab.

“The hypothesis that we had in mind was that the interaction between both cell populations is important, so both cell populations should be present,” she said.

The investigators analyzed archived or fresh tumor biopsy samples from 163 patients with untreated or previously treated NSCLC (median 3 prior lines of therapy) who were enrolled in a nonrandomized phase I/II trial evaluating durvalumab in advanced NSCLC and other solid tumors.

They matched CD8 and PD-L1 immunohistochemistry-stained sections from tissues blocks. High PD-L1 expression was defined as a 25% or higher proportion of PD-L1–positive tumor cells with membrane staining at any intensity.

The images were then evaluated with an automated system, with results matched to clinical outcomes based on the densities of CD8-positive and PD-L1–positive cells, and PD-L1 alone from pre-treatment biopsy samples using a discovery set (84 samples) and validation set (79). The datasets were matched on baseline PD-L1 status, histology, Eastern Cooperative Oncology Group performance status, lines of therapy, and response.

In a training set looking at overall response rate (ORR), they found evidence to suggest that the combination of CD8 and PD-L1 positivity was associated with a higher ORR: 42%, compared with 31% for CD8-positive expression alone, 27% for PD-L1–positive alone, and 7% for CD8-positive PD-L1–negative (less than 25% expression) alone.

They then examined the predictive ability of the combined markers, and found that over approximately 28 months of follow-up, patients with CD8-positive and PD-L1–positive dense tumors had better overall survival (median overall survival, 24.3 months), compared with PD-L1–positive only patients (median overall survival, 17.1 months), CD8-positive only patients (median overall survival, 17.8 months), or the entire patient sample (median overall survival, 11.1 months).

Similarly, progression-free survival was also better among patients with high expression of both markers (respective median progression-free survival was 7.3, 3.6, 5.3, and 2.8 months).

Dr. Althammer acknowledged that the findings were preliminary and needed to be confirmed independently in larger studies.

The study was supported by MedImmune. Sonja Althammer is an employee of Definiens AG, which is a subsidiary of MedImmune/AstraZeneca.