Supporting I–O combination therapy development with correlative assays & biomarker discovery

Immuno-Oncology Insights 2023; 4(4), 161–169

DOI: 10.18609/ioi.2023.021

Published: 15 May 2023
Interview
Ana Rosa Saez Ibanez, Samik Upadhaya


Abi Pinchbeck, Assistant Editor, Immuno-Oncology Insights, speaks to (pictured left to right) Ana Rosa Saez-Ibanez and Samik Upadhaya from the Cancer Research Institute, about their research in combination therapies across the I–O landscape and the importance of implementation of correlative assays in combination clinical trials.


What are you working on right now?

AS: One focus of my work at the Cancer Research Institute (CRI) is on our immuno-oncology intelligence database. We are constantly monitoring the drug development landscape in immuno-oncology (I–O), gathering and curating information about clinical trials in the space. We use this database to guide our clinical strategy and understand the gaps and opportunities. We also use this intelligence to inform the I–O community at large about trends in the field through regular publishing. In these publications, we dissect the space based on types of drug modalities, targeted proteins, indications, and the geography of clinical trials and sponsors. Last year, we published an update on the cell therapy landscape in oncology clinical trials, in addition to a dedicated piece on racial and ethnic diversity among patients in I–O trials. Last month, we published an update for the entire I–O clinical development landscape, and during the second half of this year, we are aiming to publish an update on the PD-1 and PD-L1 trials landscape, with an emphasis on understanding how resistance to prior I–O therapies is affecting trends in the usage of this type of treatment.SU: CRI supports the research continuum from bench to bedside, driving significant discoveries in the field of immunology and I–O. We do so by funding scientists through the postdoctoral and early-mid career levels. We also have a new program to fund investigator-initiated clinical trials and provide additional support and coordination in those studies. We place a big focus on enabling translational studies and biomarker discoveries and have been doing so in a few different ways. For instance, over the past 6–7 years, we have been supporting multi-center, science-driven Phase 1b and Phase 2 clinical trials with deep correlative studies. We like to find niches in the field that the industry may not be prioritizing, and we bring in pharma, biotech, academic investigators, and other non-profits to support these studies.

One of the studies that we are currently supporting is called REVOLUTION. This is a platform trial to evaluate different immunotherapy combinations in first-line treatment of patients with metastatic pancreatic cancer. Pancreatic adenocarcinoma is a challenging cancer type for I–O, as it is poorly immunogenic and has shown limited responses to checkpoint inhibition. Through our support, investigators are working to address this unmet medical need. We currently have three ongoing cohorts in this trial, which all have the standard of care chemotherapy, gemcitabine, paclitaxel, and ipilimumab. In addition to this, Cohort A has nivolumab, Cohort B has hydroxychloroquine, and Cohort C has a novel compound, NG-350A, which is an oncolytic virus. Cohort B has now completed enrolment, and we are waiting for the translational studies to be completed in that study. We are hopeful and excited that this study will provide much needed learning to advance the pancreatic cancer field.

AS: Another trial that we are supporting now is titled Immunotherapy Platform Study in Platinum Resistant High-Grade Serous Ovarian Cancer (IPROC). This is a Phase 2 clinical trial carried out in collaboration with the Canadian Cancers Trial Group. This ovarian cancer setting is one in which there are very limited treatment options and is a highly unmet medical need in oncology. This is considered a ‘cold’ type of tumor, so it has been difficult to treat with immunotherapy. However, we think that with the right drug combination, we can make immunotherapy work in this type of indication. IPROC is a platform study in which we are testing different promising I–O drug combinations in separate cohorts. This is done under the guidance of our drug selection committee, which is a group of academic leaders in the field of immunotherapy and ovarian oncology who help us find drug combinations with the strongest scientific rationale. An important angle of this trial is that we design a strong plan for correlative analysis to hopefully identify biomarkers of response. In the two currently open cohorts, we are working in collaboration with two companies, AstraZeneca and BioAtla, with two different combinations of a PD-L1 inhibitory antibody and an antibody-drug conjugate. We hope to see results for these two cohorts later this year. In parallel, we are exploring new I–O combinations to test in future cohorts that we want to open in the near future.SU: Yet another ongoing trial we have is to capture the tumor burden dynamics during immune checkpoint blockade using circulating tumor DNA (ctDNA). This study uses ctDNA to monitor response and potential resistance to immunotherapy, and could potentially allow patients with primary resistance to be quickly identified in real-time and redirected to alternative therapy.

The Clinical Innovator program was launched this year and is designed to investigate initiated trials that address areas of high unmet medical need in oncology. The aim is to seek mechanistic insights into patients using deeply translational correlative studies. We are targeting academic clinician scientists who have applied for this program and we have budgeted $3 million for three potential grants. CRI is aiming to coordinate these selected trials and focus on standardizing sample collection, correlative assays, and analysis. Our focus is on data sharing and the immunogenomic data that comes out of these trials is deposited into CRI’s data platform, CRI iAtlas. The CRI iAtlas is an open-source platform with data curated from various immunotherapy trials. This harmonized data set allows people to compare clinical correlates to any immunogenomic features [1]CRI iAtlas..

AS: We are also working on our company investment portfolio. Since 2021, CRI made the strategic decision to deploy part of our venture fund in early-stage private biotech companies. These must be biotech companies with a direct affiliation with CRI and have a focus on advancing immunotherapy. We have made several investments, mostly in seeds and series A companies that are working either with new I–O drug modalities or with platforms for target discovery that can be leveraged to find new immunotherapies. I am extremely excited about our growing portfolio and sharing this journey with entrepreneurs and other investing firms.

What evolution are you seeing in I–O combination therapy development and how is CRI contributing to this?

AS: Highlights of the I–O landscape publication we have recently released [2]Saez-Ibanez AR, Upadhaya S, Campbell J. Immuno-oncology clinical trials take a turn beyond PD1/PDL1 inhibitors. Nat. Rev. Drug Discov. 2023.  include the insight that companies and sponsors are pivoting away from PD-1/PD-L1 combination clinical trials. These checkpoint inhibitors have revolutionized treatment in oncology and have become a standard of care in many indications and the preferred combination partner for new assets that advance in the clinical development pipeline. This year is the first time we have seen a general decrease in the number of Phase 2 clinical trials in I–O, and this seems largely driven by a reduction in the number of trials using PD-1/PD-L1 inhibitors. This is a shift in a decade-long trend, possibly influenced by the fact that patent expiration is approaching for many of these inhibitors. This brings with it an exciting opportunity for the field to reinvent itself and keep innovating. In fact, we see an increase in Phase 1 trials, as well as more trials exploring new targets and modalities, with many drugs targeting immune cell types other than T cells. This is a fascinating time for the field.SU: Before the REVOLUTION Platform Study came to fruition, there was the PRINCE trial, which also addressed pancreatic adenocarcinoma patients. This was another I–O combination trial using chemotherapy in combination with a CD40 agonist to activate and prime the antigen-presenting cells, and a PD-1 blockade to overcome immunosuppression and invigorate the T cells for effective tumor-killing. There were three arms in the study: the CD40 agonist plus chemotherapy arm, the nivolumab plus chemotherapy arm, and the triple combination arm. The baseline immune features in patients’ blood were identified in each arm. The overall survival was close to 58% in the chemotherapy plus nivolumab arm. The impact of that trial cannot be understated – it demonstrated significant clinical benefits. More importantly, multiomic correlative analysis was performed on an unprecedented scale, and the outcome revealed some baseline immune characteristics that could predict response to each treatment arm. We are further exploring these results towards the design of a future clinical trial to guide precision treatment to stratify patients based on these identified immune signatures which will hopefully significantly increase clinical response and overall survival. 

The REVOLUTION Platform Study is based on the learnings of the PRINCE Trial with the aim to push the field even further. We also leverage our internal I–O intelligence that we have been gathering for many years to inform our clinical strategy, and we work with our investigators to figure out the right immunotherapy combinations in indications of interest.

On the clinical innovation front, we are providing a mechanism to support investigator-initiated trials, focusing on biomarker discovery and correlative assays. We are learning from both the successes and from failures where clinical signals have not been seen. Leveraging learnings from every single patient is key in our clinical efforts.

Why is the implementation of correlative assays in combination clinical trials important? What other emerging technologies can be used to speed up clinical trial development?

AS: The emerging technologies and novel trial designs that can help us bring the field forward include implementing correlative assays and creating complex translational assay plans for these trials. There is a lot of heterogeneity among patients in terms of response to immunotherapy that we do not fully understand. Correlative analysis will help us unveil what biomarkers are associated with response and what molecular pathways are involved.

Another aspect of our work that helps us move quickly in clinical trials so that we can reach more patients in a timely manner is that we design our trials as platform studies. This allows us to open a master investigational new drug (IND) and create sub-INDs to test new combination therapies in separate cohorts. This is a way to move faster in clinical trial development, as a fully new clinical trial does not need to be created each time we want to test a new combination. It also has an adaptive design, so that if we see that patients respond well in the initial enrolled cohort, we can expand that cohort and implement biomarker-driven strategies learned from the analysis of samples from the first set of patients.

In terms of other specific technologies that will help us move forward in the field, I think that ctDNA analysis holds great potential. As we see in the BR.36 trial that we are currently supporting, ctDNA can help identify, faster and more accurately than radiographic response, whether patients are responding to immunotherapy or not. Therefore, ctDNA can become a powerful decision-making tool for clinicians to decide whether to continue treatment or escalate/change therapy for patients.

Where is further improvement needed to fully realize these combination efforts? 

SU: We need to think more about how these tools can be clinically implemented for a wide uptake in the field. How can the field prepare itself to incorporate these innovative correlative studies and technologies, in addition to the learnings from them, into future clinical trials? Should there be discussions about how to make these assays into companion diagnostics in the future? We also need to work to enable the clinical application of these technologies in varying kinds of settings, not just highly specialized medical centers and clinics but also in community settings. How can these diagnostics be rapidly implemented and utilized? For instance, investigators working on our ctDNA study are constantly thinking about pragmatic approaches aimed towards the broad applicability of the findings. I think the field needs to constantly question itself and think about clinical relevance, broad applicability, and accessibility.

As the field works to further rationalize combination therapy development, what are your predictions for how the space may evolve over the next decade?

SU: Going back to the learnings from biomarkers and correlative assays, I think there will be continued focus and advancement towards biomarker-directed patient stratification approaches. Cancer is not one disease – every indication has unique biology and even within the same indication there is wide patient heterogeneity. We need to drill down further, for example, to understand the immune profile of patients, even before treatment. This involves understanding what biomarkers, immune profiles, and immune cell states these patients have and whether they can be leveraged to stratify patients into specific treatment cohorts. I think we will see a push towards more biomarker-directed precision oncology, which is a trend we have seen over the past few years in our internal analysis. I believe we will continue to see that accelerate even further.

AS: I am excited about some of the new targets and approaches emerging in immunotherapy. My prediction is that the field will diversify the ways in which it harnesses the immune system. We have seen that checkpoint inhibitors have released the brakes of the immune system by interacting with T cells. There are so many other components of the immune tumor microenvironment that we can modulate to facilitate an immune attack on the tumor. I am excited about some of the drugs targeting the tumor microenvironment and which inhibit the immune suppressive cells that are impeding the function of T cells. That is an important mechanism by which some tumors do not respond to immunotherapy.

In general, it is important to see the immune system as a complex system with many different players, some of which need to be activated, and others inhibited. Every piece needs to fall into place to achieve the desired immune function.

We also see signs of increased efforts in making drug development more patient-centric, which is the way to go. We need immunotherapies that translate well to the real world and regular clinical practice, and which allow patients to have a life as normal as possible while on treatment. Another very important angle is diversity. How can we implement diversity in clinical trials to ensure that, once drugs are approved, they can be safely administered to heterogeneous patient populations? There are many types of diversity in patients (for example related to race and ethnicity, age, or presence of comorbidities) that are necessary to integrate in clinical trials to ensure that the drugs work for all patients once they are approved. Fortunately, we see the field making increasing efforts in this direction.

What are your own goals and priorities in the same timeframe?

SU: We will continue to monitor our I–O intelligence database that keeps track of the field in terms of global drug and clinical trial development. We will continue to expand that database and adapt it to the wider field. For example, we recently published an analysis on patient diversity in I–O trials. Given that checkpoint therapy has been approved for more than a decade, we felt it was necessary to investigate the diversity in the pivotal trials that have led to FDA approvals [3]Saez-Ibanez AR, Upadhaya S, Neftelinov S et al. Population diversity in immuno-oncology trials. Nat. Rev. Drug Discov. 2022; 21(12), 870–871.. We are also continuing to assess the field to gain a more comprehensive view of the landscape in terms of biomarker usage. We have an additional focus on I–O resistance, as this is an area both driving innovation and limiting progress in the field. Our aim is to understand what is driving resistance to I–O therapies and what approaches are being undertaken to address this.

AS: Our goal is to keep expanding the support of innovative clinical concepts. We are approaching that in many ways at CRI. We have programs targeted toward academic investigators who want to pursue unique and bold ideas in investigator-initiated trials and we also have multi-centered platform studies, in which we bring several partners from academia, non-profits, big pharma, and big biotech to collaborate. We also support new small biotechs that are bringing forward fascinating new modalities in I–O. I want to keep supporting all these different strategies that work towards the same common goal.

The CRI has many patient-focused activities to increase the general understanding of immunotherapies. For example, we conduct a CRI virtual immunotherapy summit in both English and Spanish, which acts as a platform for patients to gain answers to questions about how immunotherapy works. We bring leaders in the field to explain this in layman’s terms so patients can easily understand how to find the right clinical trials for them. This is just one example of the patient-centric activities that CRI is doing as a beautiful part of our bigger goal.

SU: I would like to also take this opportunity to highlight CICON, a Cancer Immunotherapy Conference that CRI has organized since 2015. This is an international conference that academic scientists and clinicians as well as colleagues in the industry have attended in the past, and many stakeholders in the field would find it valuable [4]Seventh International Cancer Immunotherapy Conference: Translating Science into Survival..

Biographies

Ana Rosa Saez-Ibanez joined the Cancer Research Institute in 2022 as a Research Analyst at the CRI Clinical Accelerator and Venture Fund. In this role, she provides intelligence on immuno-oncology drug development trends and the competitive landscape, informing CRI’s clinical trials strategy, business development activities and start-ups investment decisions. Prior to joining CRI, Ana Rosa earned her Doctorate in Cancer Cell Biology at Uppsala University (Sweden) where she explored novel roles of receptor tyrosine kinases in promoting cancer cell migration. Following obtention of her PhD degree, Ana Rosa joined Albert Einstein College of Medicine and Icahn School of Medicine at Mount Sinai (New York) as a postdoctoral fellow, where she investigated the role of chaperone-mediated autophagy in cell fate determination and development of metastatic breast cancer. She received her BSc and MSc in Biology and Biomedicine from the University of Valencia (Spain). Over the years, Ana Rosa has cultivated an interest in the different steps of the drug development process. In 2020, she was selected for the FDA-AACR oncology educational fellowship, a competitive regulatory affairs program led by the FDA OCE. In addition, she has received training in biomedical entrepreneurship and has consulted for different investment banks as a biotech equity researcher. Finally, Ana Rosa holds a co-chair position in the fundraising committee of Women in Autophagy, a NY non-profit built to empower women and underrepresented minorities in the field of autophagy research.

Samik Upadhaya is the assistant director of scientific affairs at CRI. He is passionate about harnessing the full potential of scientific advances in cancer immunotherapy to help patients live better, longer lives. Together with the Clinical Accelerator team, he leads the program’s scientific diligence efforts, including analyses of emerging trends and challenges in the global cancer immunotherapy landscape. He assists in the team’s collaborative ventures, clinical trial design, drug development plan, and maintenance of immuno-oncology landscape databases. He is also involved in all of CRI’s research programs, and closely follows the research done by CRI grantees, evaluating their potential contributions to the field as a whole. Prior to joining CRI, Samik completed his doctoral studies in Pathology and Molecular Medicine at Columbia University where he focused on investigating the spatiotemporal dynamics of blood and immune cell production. Following his PhD, he pursued a postdoctoral research fellowship at New York University School of Medicine where he developed new techniques to visualize and analyze in vivo behaviors of stem cells of the immune system. He also received his MSc in Chemistry and a dual BSc, summa cum laude, in Biochemistry and Biomedical Sciences from Central Michigan University.

Affiliations

Ana Rosa Saez-Ibanez, PhD
Research Analyst at the Clinical Accelerator and Venture Fund,
Cancer Research Institute (CRI)

Samik Upadhaya, PhD
Assistant Director of Scientific Affairs
Cancer Research Institute (CRI)

References

1. CRI iAtlas.

2. Saez-Ibanez AR, Upadhaya S, Campbell J. Immuno-oncology clinical trials take a turn beyond PD1/PDL1 inhibitors. Nat. Rev. Drug Discov. 2023.  Crossref

3. Saez-Ibanez AR, Upadhaya S, Neftelinov S et al. Population diversity in immuno-oncology trials. Nat. Rev. Drug Discov. 2022; 21(12), 870–871.  Crossref

4. Seventh International Cancer Immunotherapy Conference: Translating Science into Survival. 

Authorship & conflict of interest

Contributions: The named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. 

Acknowledgements: None.

Disclosure and potential conflicts of interest: Saez Ibanez AR discloses she recieves support for travel and accommodation. She is fundraising committee chair for Women In Autophagy (2020–2023). She has stocks/stock options in ARVN, KYMR, AZN , XLO, VAXX, CCCC and CRBU. The author other has no conflicts of interest. 

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & copyright information 

Copyright: Published by Immuno-Oncology Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2023 Cancer Research Institute. Published by Immuno-Oncology Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: This article is based on an interview with Ana Rosa Saez Ibanez and Samik Upadhaya carried out on Mar 27 2023. 

Interview held: Mar 27 2023; Revised manuscript received: May 9 2023; Publication date:
May 16 2023


This article is part of the Combination therapy spotlight