Improving Clinical Outcomes with Rational ICT Combinations

Background

In pursuit of a deeper comprehension of the mechanisms governing both response and resistance to immune checkpoint therapy (ICT), Creative Biolabs suggests the implementation of reverse translational investigations focusing on individual agents. This approach involves studying each agent within small patient cohorts, meticulously collecting and analyzing longitudinal samples to generate hypotheses concerning immunological mechanisms. These hypotheses can then be rigorously tested in suitable preclinical models, and the resulting preclinical data can be translated into novel clinical trials. Such datasets hold the potential to furnish pertinent insights, aiding in the design of rational clinical trials and averting the shortcomings observed in unsuccessful clinical trials.

Related Strategies

Creative Biolabs has embraced this comprehensive approach to gain insights into the mechanisms governing immune responses and to steer the development of logical combinatorial strategies, as delineated below:

Addressing Primary and Adaptive Resistance Mechanisms
Prostate cancer, characterized as a "cold" tumor due to its limited mutations and T-cell antigens, exhibits primary resistance to ICT with low tumor-infiltrating T cells. Clinical trials combining ICT with agents like anti-CTLA4, without fully understanding their immunologic impact, have often failed to meet primary endpoints, revealing the need for a more nuanced approach. Studies demonstrate that while anti-CTLA4 increased tumor-infiltrating T cells, it also induced compensatory inhibitory mechanisms, leading to new hypotheses for combination therapies targeting PD-1, VISTA, and specific cytokines like IL6 and TGFβ, depending on the metastatic site, emphasizing the importance of considering organ-specific immune microenvironments in future ICT strategies.
Immunosuppressive Myeloid Cells
The immune microenvironment, unique to each tumor type, influences response and resistance to ICT. Distinct immune microenvironments were identified in ICT-sensitive and ICT-resistant tumor types, with immunologically cold tumors like prostate cancer and glioblastoma multiforme (GBM) characterized by few tumor-infiltrating T cells but a higher frequency of immune-suppressive myeloid cells. Targeting specific myeloid-associated molecules, such as CD73, chemokine receptors (CXCR4, CCR2, and CSF1R), and intracellular mediators (IDO1 and PI3Kγ), aims to promote antitumor M1 macrophages while limiting M2 macrophages, thus enhancing ICT responses by modulating macrophage differentiation. Understanding the complex signals governing this differentiation is crucial for effective targeting.
Epigenetics and Immune Response
Understanding the epigenetic regulation of immune subsets, particularly in the context of ICT, is essential. Preclinical studies revealed that EZH2, an epigenetic enzyme induced by an anti-CTLA-4 monoclonal antibody, plays a role in adaptive resistance to anti-CTLA4 therapy. Combining EZH2 inhibition with anti-CTLA4 therapy improved survival, highlighting the potential for epigenetic modulators as rational combination partners with ICT, emphasizing the importance of comprehensive tools and patient selection in developing effective treatments.

Case Study

Fig. 1 Initial phase II clinical trial combining anti-CTLA-4 and anti-PD-1 in metastatic castration-resistant prostate cancer.¹
	Metastatic castration-resistant prostate cancer (mCRPC) exhibits resistance to ICT due to limited tumor-infiltrating T cells, and previous monotherapies with anti-CTLA-4 or anti-PD-1/PD-L1 showed minimal benefit. In the largest mCRPC trial combining anti-CTLA-4 and anti-PD-1, objective response rates and overall survival varied in pre- and post-chemotherapy cohorts, with potential biomarkers of response identified, but the study also observed significant treatment-related adverse events necessitating dose/schedule modifications.
Fig. 2 Approved and emerging combinations of immune checkpoint inhibitors in therapy.²
	In efforts to surmount immune checkpoint inhibitor (ICI) resistance, a growing number of trials are investigating combination treatment strategies. This study examines the results of a new ICI combination therapy and discusses emerging innovative approaches, with a focus on future trial design aimed at optimizing patient outcomes.

Services in Creative Biolabs

Creative Biolabs provides a comprehensive range of tailored services pertaining to immune checkpoints, encompassing, yet not confined to: Biomarker Development for Immune Checkpoint Inhibitor (ICI), Immune Checkpoint Assays, Preclinical Research for Immune Checkpoint Targeting Drugs, etc. Please contact us for a thorough understanding.

References

Sharma, Padmanee, et al. "Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial." Cancer cell 38.4 (2020): 489-499.
Walsh, Robert J. et al. "Immune checkpoint inhibitor combinations—current and emerging strategies." British Journal of Cancer 128.8 (2023): 1415-1417.

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