The Sentinel

THE OFFICIAL BLOG OF THE SOCIETY FOR IMMUNOTHERAPY OF CANCER (SITC).

Tuesday, February 5, 2019

President's Message - February 2019

Dear Colleagues,

As I enter my second month as President of the Society for Immunotherapy of Cancer (SITC), I am energized in our society’s efforts to continue our growth and success into this new year. As we set the stage for the future, I wanted to offer a brief history of SITC for those new to the society, to acknowledge and celebrate our past, all made possible by a dedicated (and growing) family of SITC members.

SITC was originally founded in 1984 by 40 charter members as the Society for Biological Therapy (SBT). At the time, enthusiasm for cancer immunotherapy was driven by investigations of early cancer vaccines, interferons, interleukin-2 and other types of immune modulators. Fundamental discoveries in molecular biology and immunology over the ensuing years provided the foundation for advances in cancer immunobiology, and consequently ushered in the modern era of cancer immunotherapy, which includes transforming therapies such as the immune checkpoint inhibitors and CAR-T cells. Members of our Society were key drivers of many of these advances, in the lab and the clinic, and through critical roles within industry and government.

I attended my first meeting of the society, then SBT, in approximately 1989, and witnessed the rapid advances in understanding the nature of host anti-tumor immunity over the next decade. Based on a growing body of exciting preclinical data, many agents were brought to clinical trials by dedicated researchers, although with limited clinical success. Nevertheless, members of our society remained steadfast in their efforts to develop highly effective cancer immunotherapies. During the SBT 2002 business meeting, members voted to officially change our name to the International Society for Biological Therapy of Cancer (iSBTc). This change was enacted so that our name would reflect our emphasis and concentration on cancer while embracing and valuing our expanding member footprint across the globe. We experienced further change in 2010 when members voted to refresh the name to the Society for Immunotherapy of Cancer, a moniker that captures our focus and expertise.

The field as a whole, and our society more specifically, has come a long way in the past 35 years. Immunotherapy is not only a viable alternative to other treatments, but now in many malignancies, the most important component of treatment for cancer patients. Improved patient response rates and overall outcomes have undoubtedly played a substantial role in our society’s growth and prosperity, particularly in the past seven years. Since 2012, SITC membership has grown more than 300 percent, from 601 members to 2,457 in 2018.



The diversity of our membership has grown over the years and our society adjusted to reflect the change in composition, adding categories of nurses, pharmacists and patient advocates in recent years. In total, SITC maintains eight member categories for professional and personal classification purposes:

  • Regular
  • Affiliate
  • Emeritus
  • Nurse and Advanced Practice Provider
  • Patient
  • Patient Advocate
  • Pharmacist
  • Student and Scientist-in-Training


Historically and to this day, our regular member category is our most popular, growing to more than 1,600 professionals in the field in 2018, including basic and translational scientists and practicing oncologists. I find it interesting that while the number of regular members has increased by nearly 450 in the past three years, the category’s representation within the overall SITC membership body has actually declined by three percent since 2016. All other member categories – save emeritus, which has remained steady, comprising 18 members – have increased during the same timeframe, suggesting our reach and effect on the greater cancer community continues to grow. It is clear, though, that once a regular member joins SITC, they find a home in our society, as our retention rate among this category is a staggering 88 percent.

While we know that access to discounted registration rates at SITC programs remains a valued member benefit, our members repeatedly tell us that the ultimate rewards of a SITC membership are the indispensable professional relationships built through society involvement. These relationships expand professional networks and set the stage for meaningful collaborations that spark the next advances in the field, all with the same goal of improving patient outcomes.

I appreciate each and every one of our society’s members, many who have already renewed their memberships for the balance of 2019. Continue reading this month’s Immune Monitor to learn more about the value of a SITC membership. If you’re not currently a member, I encourage you to consider becoming a part of the SITC family.

Sincerely,















Mario Sznol, MD
SITC President

Tuesday, January 8, 2019

President's Message - January 2019

Dear Colleagues,

I am excited and honored to address you in my first monthly message as President of the Society for Immunotherapy of Cancer (SITC). I have enjoyed the past two years as SITC’s Vice President, supporting Lisa H. Butterfield, PhD, SITC’s first female president, during her tenure as leader of our society. Thank you, Dr. Butterfield, for setting a foundation for the increased inclusion, development, and celebration of women in cancer immunotherapy. The society appreciates your continued leadership and commitment to the field and our organization!

As I assume this role on the heels of another successful year for SITC – which includes reaching new marks within our membership and a record-breaking 5,000 attendees at our Annual Meeting & Pre-Conference Programs – I am looking forward to helping continue our society’s tremendous growth. During my tenure as President, I will work to sustain SITC’s commitment as the leading member association in cancer immunotherapy. I will also ensure SITC remains the host to the most important meeting in the field, as we provide a platform for the presentation of phase 1 clinical trial data that provide insight into the future of immuno-oncology.

SITC has many exciting programs and initiatives slated for the next 12 months, all of which seek to improve cancer patient outcomes by advancing the science, development and application of cancer immunotherapy. A more complete listing of these initiatives is provided below, and I would like to highlight a few occurring in the near future.

It is critical for SITC to continue its emphasis in growing the next generation of leaders in cancer immunotherapy and tumor immunology. This is an area I am keenly focused on and support heavily. To that end, SITC is pleased to continue to offer SITC Fellowship Awards in 2019. Made possible through generous support from our industry partners, SITC Fellowships honor some of the brightest young minds in the field. The development and celebration of young investigators in our field is an important strategic priority of the society and one of my foci as President.

Additionally, registrations are open for SITC’s first Cancer Immunotherapy Winter School. Scheduled for Feb. 18-22 in Mesa, Ariz., this new program, tailored to early career scientists and clinicians as well as those new to the field, will teach the fundamentals of cancer immunotherapy and allow attendees to choose from a variety of tracks that focus on topics most relevant to them. Space is limited so register early! Also, SITC will host its first Meet-the-Expert Webinar on Thursday, Jan. 17 at 12:30 p.m. CST. This hour-long webinar, moderated by Sruthi Ravindranathan, PhD (Emory University), and with participation from presenter Vionnie W.C. Yu, PhD (Novartis Institutes for Biomedical Research), will focus on the topic Careers in Industry. Please click here to register for this free online event.

SITC continues its 2018-19 Advances in Cancer Immunotherapy™ (ACI) regional education program series, with events currently confirmed for Sacramento, Calif., on Jan. 10 in Houston on Feb. 9 and in Portland, Ore., on Feb. 21. Also, we look forward to hosting two, back-to-back thoughtful and engaging interim workshops, focused on cancer immune responsiveness and resistance; and adoptive cellular therapy. Stay tuned for information regarding location, registration and lodging.

If you haven’t already, I hope you’ll consider joining or renewing your SITC membership in 2019 to enjoy a variety of member benefits, including early access to register for the 34th Annual Meeting & Pre-Conference Programs, scheduled for Nov. 6-10, 2019, in National Harbor, Md.

I am excited to strengthen existing, and build new, relationships with leaders in the field as we work together to continue the growth and success of the society.

Sincerely,















Mario Sznol, MD
SITC President

Thursday, December 6, 2018

President's Message - December 2018

Dear Colleagues,

In my final Society for Immunotherapy of Cancer (SITC) Presidential Message, I thought I’d start with last month’s 33rd Annual Meeting & Pre-Conference Programs (SITC 2018). We welcomed 5,000 attendees; the society’s highest number to date. Also, SITC now has more than 2,400 society members – the highest number in our history, including researchers, clinicians, patient advocates and students. I would be remiss if I did not express my sincere appreciation to all of our funders who contributed to our success by supporting our many educational programs in 2018. The full list appears below. It has really been an extreme period of growth, both within our society as well as the field in general, and support from our partners has been instrumental.

It has been an honor and a pleasure to serve as SITC President, for these last two years, and I look forward to the leadership of Mario Sznol, MD, as incoming President and to continuing to participate in society leadership as Immediate Past President for two more years. This position has allowed me to participate in many field-wide initiatives around both the science (immune biomarkers, SITC Cancer Immunotherapy Winter School, immune responsiveness, cellular therapies, the SITC textbook) and the people in it (women’s networking, young investigators, international outreach, among others). It has put me around the table with my academic colleagues, pharma and biotech collaborators, leaders of related societies and NCI and FDA colleagues to discuss how we can work together towards our shared goals of meaningful science and therapies for patients. All of this work has been enabled and supported by all of you, the staff of SITC and especially Tara Withington, CAE, SITC’s Executive Director.

There has been important progress in the last several years, and there is much more to do. SITC will be a vehicle supporting progress for years to come, and I look forward to working with you all to make it happen.

Sincerely,














Lisa H. Butterfield, PhD
SITC President

Monday, November 12, 2018

SITC 2018 Scientific Highlights - Nov. 11

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 11, 2018, sessions of the 33rd Annual Meeting.

 

Phase 1b/2 Data Suggest Promising Efficacy and Safety of Anti-NKG2A Monalizumab in Combination with Cetuximab for the Treatment of Patients with Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck  


Roger Cohen, MD (Abramson Cancer Center, Philadelphia, PA, USA), reported on a phase 1b/2 clinical trial (NCT02643550) evaluating the safety and efficacy of anti-NKG2A monalizumab in combination with cetuximab in patients who have received prior systemic therapy for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). As of August 31, 2018, 40 total patients were enrolled (Progressive disease after platinum, 75 percent are HPV negative, 43 percent prior IO therapy, 33 percent are IO resistant) and received monalizumab (10 mg/kg Q2W) in combination with cetuximab (400 mg/m2). Median overall survival (OS) was 10.3 months and 12.8 months in IO naïve (n=23) and prior IO patients (n=17), respectively. Median progression-free survival (PFS) was 4.0 months and 5.0 months in IO naïve and prior IO patients, respectively. Overall response rate (ORR) was 27.5 percent (95 percent CI, 16.1-42.8) in all patients with one confirmed complete response (CR) and ten confirmed partial responses (PR). Responses to therapy were observed in both IO naïve (35 percent [95 percent CI: 19 – 55]) and IO pretreated patients (18 percent [95 percent CI: 6 – 41]). Median duration of response (DOR) was 5.6 months (95 percent CI: 3.8 – not yet reached). Combination-related adverse events (AEs) were mostly grade 1-2. Only one patient required cessation of treatment secondary to treatment related toxicity, with no observed potentiation of cetuximab-related AEs. Additionally, stromal NK cell and tumor CD8+ T cell infiltration was observed 15 days after first administration of combination treatment in all responding patients. Together, these data suggest combination monalizumab and cetuximab is safe and may be effective in treating patients with both IO naïve and IO pretreated R/M SCCHN. 

OX40 and CD137 Dual Agonist Bi-specific Antibody FS120 mAb2 Activates T cells and Promotes FcγR-independent Anti-tumor Activity in Pre-clinical Models


Miguel Gaspar, PhD (F-star Biotechnology, Cambridge, UK), described the anti-tumor activity of FS120 mAb2 – a bi-specific antibody that targets the co-stimulatory tumor necrosis factor receptor (TNFR) superfamily receptors OX40 and CD137. OX40 and CD137 are expressed on CD4+ and CD8+ T cells as well as NK cells, suggesting that the ligation of the receptors may help activate various types of immune cells. However, FcγR-mediated crosslinking is also necessary for monoclonal antibodies to induce receptor clustering and immune activation. To overcome this issue, FS120 mAb2 was generated by introducing an OX40-binding site into the Fc-region of a human IgG1 targeting CD137. Data indicate FS120 mAb2 concurrently binds to OX40 and CD137 in pre-clinical models with subnanomolar affinity and stimulates both CD4+ and CD8+ T cells in the absence of FcγR crosslinking. FS120 mAb2 demonstrated increased anti-tumor activity than a combination of OX40 and CD137 monoclonal antibodies in the CT26 mouse tumor model (p less than 0.00001). In addition, doses as low as 1 mg/kg of FS120 mAb2 induced peripheral T cell activation and proliferation without regulatory T cell depletion in CT26 and B16-F10 syngeneic models. Together, these data suggest that FS120 mAb2 can stimulate both CD4+ and CD8+ T cells, mediating potent FcγR-independent anti-tumor activity, and support initiation of future clinical development.  

Pre-clinical Studies Suggest Removal of Terminal Sialic Acids of Sialoglycans with EAGLE may Enhance Anti-PD-1 Efficacy 


Li Peng, PhD (Palleon Pharmaceuticals, Waltham, MA, USA), presented research describing EAGLE (enzyme-antibody glycan-ligand editing) - a novel multi-functional antibody-like molecule that inhibits the glyco-immune checkpoint axis by selectively removing the terminal sialic acids of sialoglycans on tumor cells. Recent data suggest that the glyco-immune checkpoint axis (sialoglycan/Siglec pathway) may serve as a target to alter immunity within tumor microenvironment. Ligation of sialylated glycans to ITIM (immune receptor tyrosine-based inhibitory motif)-containing Siglecs on immune cells regulates functions of macrophages, monocytes, dendritic cells, T cells, and NK cells. In this study, multiple EAGLE variants were shown to reduce tumor growth in mice bearing EMT6-Her2 syngeneic subcutaneous/orthotopic breast cancer tumors, achieving 7/24 CR. Further experiments revealed that EAGLE treatment decreased sialic acid levels on tumor cells, leading to increased immune cell infiltration and activation as well as induction of anti-tumor immunological memory. EAGLE pre-clinical efficacy was reduced by depletion of NK cells, macrophage, and CD8+ T cells. Interestingly, treatment with EAGLE or the combination of anti-PD-1 and anti-CTLA4 achieved similar anti-tumor activity in mice bearing the “cold” poorly immunogenic B16D5-Her2 tumor model. Importantly, EAGLE + anti-PD-1 was more effective at eradicating tumors than the respective monotherapies (6/6 CR = EAGLE + anti-PD-1, 3/6 CR = EAGLE, 2/6 = anti-PD-1). These data demonstrate pre-clinical efficacy of EAGLE as a monotherapy and in combination with anti-PD-1, and suggest that EAGLE may favor induce immunity against “cold” tumors. 

Novel Hexavalent Fusion Protein HERA-GITRL Promotes T cell Expansion and Anti-tumor Activity in Humanized Mouse Models 


David Richards, PhD (Apogenix AG, Heidelberg, Germany), presented data detailing the effects of HERA-GITRL - a hexavalent human glucocorticoid-induced tumor necrosis factor receptor (TNFR) ligand fusion protein - to increase T cell stimulation and subsequent anti-tumor activity. Pre-clinical data indicate that agonizing the TNFR super family member GITR can induce anti-tumor T cell activation and may be a promising cancer immunotherapy strategy. HERA-GITRL is composed of a trivalent single chain GITRL-receptor-binding-domain fused to an IgG1-derived silenced Fc-domain that serves as a multimerization scaffold. In vitro analyses showed that HERA-GITRL increases activation, maturation, and proliferation of CD4+ and CD8+ T cells, naïve and memory T cells, without affecting regulatory T cells (Tregs), and can prevent Treg-mediated suppression. In pre-clinical in vivo antigen-specific adoptive transfer assays, surrogate murine HERA-GITRL (5 mg/kg) increased expansion of antigen-specific CD4+ and CD8+ T cell populations compared to control treatment (CD8+ = 3.5 percent vs 1.3 percent; CD4+ = 4.2 percent vs 2 percent), and did not stimulate non-specific immune cell expansion. Treatment of CT26 cancer models with HERA-GITRL (1mg) reduced tumor growth compared to placebo. HERA-GITRL-mediated T cell activation enhanced tumor cell killing independent of Fc functionality in vitro as well as in humanized mouse models. These pre-clinical data suggest that HERA-GITRL may be able to enhance antigen-specific T cell activity and anti-tumor efficacy.  


Sunday, November 11, 2018

SITC 2018 Scientific Highlights - Nov. 10


The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 10, 2018, sessions of the 33rd Annual Meeting.

Kristin Anderson, PhD (Fred Hutchinson Cancer Research Center), delivers her
SITC 2018 Presidential Session presentation on Saturday, Nov. 10, 2018.

The Novel Oncolytic Virus Voyager V1 is Safe and Promotes Immunity in Patients with Solid Tumors

Steven F. Powell, MD (Sanford Health, Sioux Falls, SD, USA) detailed first-in-human data for application of the novel oncolytic virus Voyager V1 (VV1) for treatment of patients with solid tumors including squamous cell carcinoma of the head and neck, colon, rectal, pancreatic, and breast, among other cancers. VV1 is derived from the vesicular stomatitis virus and encodes IFNbeta to help amplify anti-tumor efficacy, as well as the thyroidal sodium iodide symporter NIS gene to allow for noninvasive imaging of virus dissemination. Administered as a one-time intratumoral injection, VV1 was well tolerated in patients with 80% of treatment related AEs reported being short-lived as well as mild to moderate in severity. Interestingly, VV1 proliferation and spread, determined by positive SPECT/CT within the tumor, was more readily observed in colorectal and pancreatic cancers compared to other diseases. Additionally, IFNbeta was detected in the serum of patients treated with high VV1 doses, indicative of viral replication within the tumor. Importantly, there was evidence of intratumoral inflammation in 75% of evaluable patients, and T cell infiltration was observed up to 29 days post-therapy in non-injected lesions. Overall, these data indicate that VV1 is well tolerated as a single-agent, and that it may promote inflammation and immunity at both injected and non-injected tumors. Having demonstrated synergistic effects with anti-PD-1/PD-L1 antibodies in preclinical models, future evaluations of VV1 in combination with the anti-PD-L1 avelumab are planned.

Chop Directly Regulates T-bet Transcription to Control T cell Motility

Yu Cao, PhD (H. Lee Moffitt Cancer Center, Tampa, FL, USA) discussed research evaluating the role of C/EBP-homologous protein Chop in the regulation of CD8+ T cell effector function in the tumor microenvironment. Data indicate that Chop is upregulated in tumor-associated CD8+ T cells from human ovarian cancer samples, but not in circulating CD8+ T cells. Furthermore, ovarian cancer patients with CD8+ T cells expressing high-levels of Chop have reduced survival compared to patients with Low-Chop expressing intra-tumor CD8+ T cells (p = 0.05). Next-generation sequencing analyses revealed overexpression of signatures associated with effector function in Chop-negative CD8+ T cells. Accordingly, Chop-negative CD8+ T cells displayed increased anti-tumor activity. Further experiments showed that Chop deletion in T cells results in increased expression of T-bet – the master regulator of effector T cell function. Interestingly, a Chop binding site was identified within the promoter region of T-bet, and subsequent experiments revealed that Chop in fact binds to T-bet promoter and directly inhibits T-bet transcription. Finally, adoptively transferred Chop-negative CD8+ T cells more efficiently controlled tumor growth in B16-bearing mice compared to Chop-positive cells. Together, these data suggest that Chop directly inhibits T-bet transcription and regulates CD8+ T cell effector function, offering a new potential target to augment immunotherapeutic efficacy.

Phase 1b Data Reveal Early Signs of Safety and Efficacy of the A2AR Antagonist CPI-444 as Monotherapy and in Combination with Atezolizumab in Patients with Renal Cell Carcinoma

Lawrence Fong, MD (University of California, San Francisco, CA, USA) reported data from a phase 1b clinical trial (NCT02655822) evaluating CPI-444 - an oral antagonist of the adenosine 2A receptor (A2AR) - as monotherapy or in combination with anti-PD-L1 atezolizumab for the treatment of patients with relapsed/refractory renal cell carcinoma (RCC). Patients (median three prior treatments, 71 percent prior-immunotherapy) received either CPI-444 (100mg BID) as a monotherapy (n=33) or in combination with atezolizumab (800 mg Q2W, n=35). At median follow up of 8.7 months, overall survival was 65% and 88% for the monotherapy and combination cohorts, respectively. In addition, median progression-free survival in the monotherapy cohort was 4.1 mos, and 5.8 mos patients receiving combination CPI-444 + atezolizumab. 6-month disease control rates (DCR) were 25% and 32% for the monotherapy and combination cohorts, respectively. Median time to best tumor response was 3.4 months for the monotherapy cohort and 5.5 months for the combination cohort. CPI-444 was well tolerated with mostly low-grade treatment-related adverse events. Increased CD8+ T cell infiltration positively correlated with improved 6-month DCR. Analyses revealed that clinical response was only seen in patients with high tumor-adenosine signatures. In summary, data suggest early clinical benefit of CPI-444 monotherapy or in combination with atezolizumab in patients with relapsed/refractory RCC, and that tumor adenosine gene signatures may be a potential biomarker of response. 

Targeting FasL using an Immunomodulatory Protein May Help Increase Persistance of Adoptive TCR T cell Therapies

Kristin Anderson, PhD (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) presented data demonstrating how an immunomodulatory fusion protein targeting Fas ligand (FasL) can enhance survival of adoptive TCR-transduced T cells in a pre-clinical ovarian cancer model. In collaboration with Dr. Philip Greenberg's group, Dr. Anderson utilized adoptive T cells that harbor a genetically-engineered TCR receptor targeting mesothelin (TCR-Mslin) as a potential therapeutic to treat patients with ovarian cancer. Results indicate that TCR-Mslin T cells have anti-tumor activity in vitro, but have limited persistence and reduced effector function in pre-clinical ID8-VEGF tumors that mimic human ovarian cancer phenotypes. Multiple adoptive transferes of TCR-Mslin T cells increased survival of mice bearing ID8-VEGF tumors, but this strategy has limited translational potential in humans. As such, Anderson’s group developed a FasL/4-1BB immunomodulatory fusion protein to help increase CD8+ T cell proliferation and survival. FasL/4-1BB CD8+ T Cells had increased proliferation ability, as well as increased cytokine secretion including IFNgamma and TNFalpha. Enhanced survival was noted in mice bearing ID8-VEGF tumors who received adoptive transfer of TCR-Mslin + FasL/4-1BB T cells when compared to mice receiving TCR-Mslin or WT CD8+ T cells. In all, these early data suggest that the described FasL/4-1BB immunomodulatory protein may help increase survival of TCR-transduced CD8+ T cells, and may be a potential technology to help facilitate movement of TCR-T cells into the clinic.  

PAK4 Regulates Immune Cell Infiltration to Increase Tumor Response to Anti-PD-1 Blockade

Gabriel Abril-Rodriguez (UCLA, Los Angeles, CA, USA) discussed analyses of tumor samples from patients with metastatic melanoma treated with anti-PD-1 therapy to help identify mechanisms leading to tumoral immune cell exclusion. RNAseq analyses performed on tumor samples from 41 melanoma patients demonstrated that low CD8+ T cell and dendritic cell infiltration an inverse correlation correlate with upregulation of P21 activated Kinase 4 (PAK4). PAK4 is a kinase that binds to and phosphorylates beta-catenin to activate Wnt signaling, and is known to be involved in tumorigenesis. This observation was further supported by analyses of TCGA gene expression data from 32 cancer types showing a negative correlation between PAK4 expression and clinical responses in patients with melanoma, prostate cancer, and pancreatic cancer, among others. Syngeneic C57BL/6 mice bearing B16 PAK4 knockout tumors were sensitized to PD-1 inhibition compared to mice bearing B16 wildtype tumors that were resistant to checkpoint blockade, and PAK4 knockout tumors displayed increased CD8+ and dendritic cell infiltration compared to WT tumors. Anti-PD-1 efficacy was lost upon depletion of CD8+ T cells in PAK4 knockout tumors. Importantly, treatment of B16 melanoma models with anti-PAK4 and anti-PD-1 significantly reduced tumor growth compared to mice treated with each agent alone. Together, these data suggest that PAK4 may contribute to tumor immune evasion, and that inhibition of PAK4 may help overcome resistance to PD-1 blockade.

B cell Signatures may Predict Response to Neoadjuvant Immune Checkpoint Blockade in Melanoma and Renal Cell Carcinoma Patients

Sangeetha Reddy, MD, MSci (MD Anderson Cancer Center, Houston, TX, USA) presented research towards the identification of immune cell profiles of response in patients from a randomized trial (NCT02519322) evaluating efficacy of neoadjuvant immune checkpoint blockade in patients with high-risk resectable melanoma. A total of 23 patients were randomized to receive neoadjuvant nivolumab (n = 12) or neoadjuvant ipilimumab + nivolumab (n = 11), and tumor samples were analyzed using transcriptomic profiling. Typical biomarkers associated with response to immune checkpoint inhibitors – including PD-L1 and CD8 – were observed in patient tumor samples. Interestingly, tumor B cell signatures were also differentially expressed according to patient response, including MZB1, JCHAIN, and IGLL5 (p less than 0.0001 for each). B cell lineage score was also correlated with improved survival, especially in patients who had low CD8+ T cell signatures in their respective tumor samples. Interestingly, data from a similar trials evaluating neoadjuvant immune checkpoint inhibition in patients with metastatic RCC (NCT02210117), as well as melanoma samples within the TCGA dataset displayed immune signature patterns to the observed melanoma trial dataset. Multiplex immunohistochemostry of tumor sections from the melanoma trial cohort demonstrated co-localization of the B cells and CD8+, CD4+ T cells, as well as CD21 follicular dendritic cells, in tertiary lymphoid structures or responders (p = 0.037 at baseline, p = 0.002 on-treatment). Together, these results suggest that B cell genetic signatures may serve as prognostic and predictive biomarkers for response to neoadjuvant immune checkpoint blockade.  

Increased Abundance of CD8+ Stem Memory Cells Correlates with Response in Melanoma Patients Treated with Adoptive TIL Therapy

Matthew Beatty (Moffitt Cancer Center, Tampa, FL, USA) detailed novel data describing how enrichment of CD8+ stem memory T cells (Tscm) in adoptive T cell therapy products associates with response in patients with advanced melanoma. In all, 57 patients with stage IV melanoma (anti-PD-1 naïve) were enrolled across four trials and 47 patients received adoptive therapy with tumor-infiltrating lymphocytes (TIL). Overall response rate (ORR) in the treated patients was nearly 39 percent. Interestingly, CD8+ Tscm cell and overall TIL persistence were increased in patients with complete or partial response compared to patients who demonstrated stable or progressive disease (per RECIST). Increased five-year PFS (36.5 months) was observed in patients with high levels of Tscm (greater than 7.81 percent), compared to patients with low levels of Tscm (less than 7.81 percent; seven months). Furthermore, T cell clones derived from infusion product CD8+ Tscm were shown to persist/expand in vivo at six weeks post-infusion, and there was a positive association between CD8+ Tscm abundance and one-year clinical response. In addition, purified patient CD8+ Tscm demonstrated anti-tumor reactivity as well as ability to differentiate into additional memory T cell subsets six weeks post-infusion. In summary, CD8+ Tscm abundance in adoptive TIL infusion products may indicate increased anti-tumor efficacy in patients with advanced melanoma who have not received prior anti-PD-1 treatment.

IL10 and IL35 may Regulate CD8+ Inhibitory Receptor Expression Through BLIMP1

Hiroshi Yano, BS (University of Pittsburgh, Pittsburgh, PA, USA) presented research investigating the cooperative regulation of anti-tumor immunity in the tumor microenvironment by IL35 and IL10. Researchers discovered that deletion of IL10, IL35, and IL10/IL35 similarly lead to reductions in in vivo B16-melanoma growth. Interestingly, IL10 and IL35 deficiency individually reduced CD8+ inhibitory receptor expression – including TIM3, TIGIT, and PD-1. IFNgamma and TNFalpha secretion, however, were differentially regulated by IL10 and IL35, as well as CD8 memory T cell differentiation. Towards elucidating a potential mechanism, Yano’s group analyzed CD8+ T cell subsets from IL10 and IL35 deficient mice and noted increased expression of BLIMP1 – a known regulator of T cell inhibitory receptor expression. Further experiments demonstrated that IL10 and IL35 directly inhibit BLIMP1 expression, thus explaining CD8+ T cell inhibitory receptor down-regulation in IL10 and IL35 deficient mice. Together, these data help describe a mechanism of how IL10 and IL35 can contribute to CD8+ T cell anti-tumor activity through direct regulation of BLIMP1 and control of inhibitory receptor expression, but also differentially regulate cytokine secretion and memory cell expansion.

Saturday, November 10, 2018

SITC 2018 Scientific Highlights - Nov. 9



The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the first day of the 33rd Annual Meeting in Washington, D.C.


Oxygen Concentration Influences T cell Motility within Solid and Hematologic Malignancies

Tomasz Zal, PhD (MD Anderson Cancer Center, Houston, TX, USA) presented research investigating the effect of oxygen concentrations upon T cell motility within tumors. Previous research suggests that hyper-oxygenation can improve response to immunotherapy, but its effects upon T cell motility are unknown. To investigate this question, Dr. Zal described the development of a novel microscopy method that allows for measurement of oxygen concentrations using a novel FaST-PLIM method - based upon PtP-C343 phosphorescence lifetimes - while simultaneously assessing T cell motility. Initial evaluation of bone marrow samples from patients with acute lymphoblastic leukemia (ALL) using this approach revealed that T cell motility is reduced in hypoxic regions, specifically with oxygen pressure less than 5 mmHg. Regions with oxygen pressure greater than 5 mmHg contained T cells with normal T cell motility. In support, T cell motility in solid lung tumor samples was also decreased in regions with oxygen pressure less than 5mmHg. Interestingly, treatment of an ALL mouse model with an inhibitor of oxidative phosphorylation (IACS-10759) increased oxygen concentrations within the bone marrow, but did not restore T cell motility. In contrast, supplementation of oxygen to the lung tissues increased oxygen pressure and recovered T cell motility. Together, these data suggest that T cell motility is reduced in hypoxic regions of tumors, and that hyper-oxygenation can restore T cell surveillance that could potentially enhance immunotherapeutic efficacy.

Meta-Analysis Reveals Correlations Between Response to Anti-PD-1/PD-L1 Therapy and Biomarker Assessment Methods

Steve Lu, BS (Johns Hopkins University, Baltimore, MD, USA) presented data from a meta-analysis comparing associations between response to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) and specific biomarker assessment methods including PD-L1 immunohistochemistry (IHC), tumor mutational burden (TMB) evaluation, gene expression profiling (GEP), and multiplex immunofluorescence (IF). In all, data from 8021 patient samples from greater than 10 tumor types (44 published studies total) were included in the analysis, with investigators noting the type of biomarker analysis used in the study as well as the number of patients with complete response, partial response, and progressive disease. Results indicate that multiplex IF was more significantly correlated with ICI response (weighted AUC = 0.802) than PD-L1 IHC, TMB, and GEP (weighted AUC = 0.656, 0.690, 0.652, respectively). A combined approach using a combination of PD-L1 IHC, TMB, and/or GEP enhanced association with ICI response compared to the respective individual approaches (AUC = 0.733), but multiplex IF remained the strongest correlative (AUC = 0.802). This meta-analysis suggests a current hierarchy of biomarker assessment and association with ICI response. Further studies are necessary to validate these findings for each individual and combinatorial approach, and identified ICI response associations will remain in flux as new technologies become available.

Visualization of Tumors and CD8+ T cell Distribution in Patients with Advanced Solid Tumors via a Novel Anti-CD8 Minibody

Michael Gordon, MD (HonorHealth Research Institute, Scottsdale, AZ, USA) presented initial data from a phase 1 first-in-human study investigating a novel method to detect CD8+ T cell distribution in patients with solid tumors using positron emission tomography and the anti-CD8 radiolabeled minibody 89Zr-IAB22M2C. In all, 15 patients with advanced solid tumors (melanoma = 8, non-small cell lung cancer [NSCLC] = 6, hepatocellular = 1) were provided 89Zr-IAB22M2C (0.5-1.5mg, 3mCi IV) and subsequently underwent multiple PET scans over a 5-7 day period (scans = 1-2hr, 6-8hr, 24hr, 48hr, 5-7 days). No drug-related adverse reactions during administration of 89Zr-IAB22M2C were noted, with the exception of transient ADA in one patient. PET results indicate that 89Zr-IAB22M2C readily accumulates in CD8-rich tissues including bone marrow and the spleen, and that excess 89Zr-IAB22M2C was excreted through the hepatobiliary system. Tumor 89Zr-IAB22M2C uptake was noted in 10/15 patients, and very little signal was observed in background tissues including muscle, brain, and heart. 89Zr-IAB22M2C signal was observed over several days (at least day 7), and more clearly identified a secondary lesion in a patient with hepatocellular carcinoma compared to hepatic phase CECT. Together, these data indicate that 89zr-IAB22M2C is safe in patients with advanced solid tumors, and may be able to provide assistance in measuring tumor size and location, as well as CD8+ T cell distribution.

Early Phase 1 Data Suggest Combination Anti-TIM-3 and Anti-PD-1 Offers Promising Safety and Efficacy in Patients with NSCLC Treated with Prior Anti-PD-1/PD-L1 Therapy

Diwakar Davar, MD (University of Pittsburgh, Pittsburgh, PA, USA) presented data from the phase 1 AMBER trial (NCT02817633) assessing dosage, safety, and efficacy of TSR-022 – an anti-TIM3 monoclonal antibody – in combination with anti-PD-1 TSR-042 in patients with advanced NSCLC who have relapsed or are refractory to prior anti-PD-1/PD-L1 therapy. In all, 39 patients (prior pembrolizumab = 14, prior nivolumab = 23, prior atezolizumab = 5, others = 2; PD-L1 TPS greater than or equal to one percent = 16, TPS less than one percent = 8, unknown TPS = 15) received TSR-022 (100mg: n=14; 300mg: n=25, Q3W) in combination with TSR-042 (500mg Q3W). Treatment-related adverse events were observed in less than five percent of patients, with only three grade three events (100mg cohort: one fatigue, one lipase increase; 300mg cohort: one lipase increase). In all, four PR and 11 SD were observed in 31 evaluable patients across both cohorts (100mg: one PR, three SD; 300mg: three PR, eight SD). Interestingly, all four PR were observed in patients with PD-L1 TPS greater than or equal to one percent. Together, these data indicate that combination TSR-022 + TSR-042 is safe in patients with advanced NSCLC who have received prior anti-PD-1/PD-L1 therapy, and early signs of clinical efficacy support continued investigation of this treatment regimen. In addition, these data suggest that PD-L1 TPS may serve as a predictive biomarker of response for this combination strategy.

Phase 1 4280-001 Trial Offers Early Glimpse into Safety and Efficacy of Treatment of Patients with Advanced Solid Tumors with Anti–LAG-3 MK-4280 as a Single-Agent or in Combination with Pembrolizumab

Nehal Lakhani, MD, PhD (START-Midwest, Grand Rapids, MI, USA) presented data from the first-in-human phase 1 4280-001 trial (NCT02720068) investigating dosage and safety of the anti-LAG-3 antibody MK-4280 as a single-agent or in combination with anti-PD-1 pembrolizumab for the treatment of patients with advanced solid tumors. Adult patients with metastatic solid tumors (sarcoma, appendiceal, billary, colorectal, adrenocortical, breast, small intestinal, renal cell, among others) received MK-4280 (dose-escalation from 7 - 700mg Q3W) as a single agent (n = 18) or in combination with pembrolizumab (200mg Q3W, n = 15). No dose-limiting toxicities were observed in either cohort across all MK-4280 doses. Grade 3 TRAEs were observed in 50 percent (n=9) and 60 percent (n=9) of the monotherapy and combination cohorts, respectively. At data cut-off, ORR was six percent (95 percent CI: less than one – 27; one PR, two SD) in the monotherapy cohort, and 27 percent (95 percent CI: 8 – 55; four PR, 2 SD) in the combination cohort. Disease control rate was 17 percent (95 percent CI: 4 – 41) and 40 percent (95 percent CI: 16 – 68) in patients who received MK-4280 and MK-4280/pembrolizumab, respectively. These early data suggest that MK-4280 can be safely provided to patients with advanced solid tumors up to 700mg, and that administration as a single-agent or in combination with pembrolizumab may potentially provide clinical benefit.

Updated PIVOT-02 Results Demonstrate Durable Responses in Advanced Melanoma Patients Treated with NKTR-214 + Nivolumab

Adi Diab, MD (MD Anderson Cancer Center, Houston, TX, USA) presented updated data from the PIVOT-02 (NCT02983045) trial assessing efficacy and safety of the IL-2 agonist NKTR-214 in combination with anti-PD-1 nivolumab for the treatment of patients with advanced melanoma. In all, 38 patients (PD-L1 greater than or equal to 1 percent = 19, PD-L1 less than one percent = 14) treated with NKTR-214 (0.006 mg/kg Q3W) and nivolumab (360 Q3W) displayed an ORR of 53 percent (n = 20, CR = 9, PR = 11). ORR of PD-L1+ and PD-L1- patients was 68% and 43%, respectively. At median follow-up of 7.2 months, median duration of response has not yet been reached (95 percent CI: 2.6 – NR), and 85 percent (17/20) of patients have ongoing responses. Grade 3/4 TRAEs were observed in 8 patients (19.5 percent), most commonly lipase increase (n = 3) and atrial fibrillation (n = 2). Importantly, incidence of cytokine-related AEs – a concern with traditional IL-2 treatment – decreased over continued dosing. Analyses of patient peripheral blood revealed increases in CD4+ (15x, p less than 0.001), CD8+ (26x, p less than 0.001), and NK cells (4.5x, p less than 0.001) seven days post-cycle 1. Increased tumor infiltration of CD8+ T cells was also observed in patients treated with the combination regimen (baseline = 108 cells/mm2; week 3 = 712 cells/mm2). Gene expression analyses of treated patient samples also indicate a profile consistent with CD8+ anti-tumor activity. In all, these data suggest that NKTR-214 + nivolumab may provide clinical benefit as first-line treatment of patients with advanced melanoma, and that the combination promotes increased immunity within the tumor microenvironment.

Inhibition of MARCO may help Promote Anti-Tumor Activity within the Tumor Microenvironment

Dhifaf Sarhan, PhD (Karolinska Institutet, Solna, Sweden) described the role of the scavenger receptor MARCO (macrophage receptor with collagenous structure) towards modulation of immunity within tumor microenvironment. MARCO is expressed on suppressive immune cells including myeloid-derived suppressor cells and tumor-associated macrophages, commonly found in pancreatic cancer samples that also have low CD8+ T cell infiltration. Pre-clinical studies reveal that treatment of mice bearing 4T1 mammary carcinoma with an anti-MARCO antibody reduced tumor growth and metastasis. The mechanism of action, however, remains unknown. Evaluation of pancreatic cancer samples revealed that low abundance of MARCO correlated with increased T cell infiltration and survival compared to MARCO-high samples (p = 0.033 and 0.027, respectively). In addition, treatment of cytokine-polarized macrophages that display a suppressive phenotype with anti-MARCO restored IFNgamma production as well as tumor killing function, and normalized metabolism towards the levels of M1 anti-tumor macrophages. Together, these data showed that increased MARCO abundance on TAMs and MDSC may inhibit cytotoxic anti-tumor activity in the tumor microenvironment, and that treatment of patients with anti-MARCO may be a potential approach towards restoring immunity in difficult to treat diseases such as pancreatic and breast cancer.

Personalized NEO-PV-01 Vaccine Promotes Immunogenic Responses in Patients with Advanced Melanoma and NSCLC

Siwen Hu-Lieskovan (Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA) presented clinical data from the phase 1b NT-001 trial (NCT02897765) investigating efficacy of NEO-PV-01  – a personalized neoantigen vaccine that targets up to 20 unique, high quality neoantigens – in combination with nivolumab for the treatment of patients with metastatic melanoma and NSCLC. Patients received initial nivolumab for 12 weeks while NEO-PV-01 was synthesized, and then received the vaccine for an additional 12 weeks. All patients developed an immune response due to the vaccination, and 56 percent of epitopes were able to induce a CD4+ and CD8+ immune response that was detectable two weeks into treatment. 50 percent of melanoma patients achieved PR prior to NEO-PV-01 vaccination, and an additional 37 percent and 6.3 percent achieved PR and CR post-vaccination, respectively. In all, 75 percent of melanoma patients remain on treatment. In addition, 27 percent of patients with NSCLC achieved PR pre-vaccination, and an additional 25 percent achieved PR post-vaccination. 64 percent of NSCLC patients remain on treatment. Two melanoma patients treated with the combination regimen demonstrated durable responses that were detectable 52- and 70-weeks post treatment initiation, and one NSCLC patient experienced an immune response detectable 52 weeks post-initiation of therapy. In summary, data suggest that the NEO-PV-01 vaccination in combination with nivolumab may be effective in treating patients with melanoma and NSCLC, and that immunity generated by the vaccine is durable over time.