Current Immunotherapy Progress With Adoptive Cellular Therapies and Combinations

Patrick Hwu, MD

The clinical development and application of cancer immunotherapy over the past decade has translated the long-standing knowledge of the close relationship between cancerous tissues and lymphoid immune cells, dating back to the late 19th century.^1,2

Today, cancer immunotherapies, all of which recruit the body’s own immune system to target and eliminate cancer cells, represent a rapidly expanding and paradigm-shifting arsenal in cancer treatment. Immunotherapies that have gained regulatory approval and/or are in clinical development include immune checkpoint blockade agents, chimeric antigen receptor (CAR) T cell therapy, cancer vaccines, and adoptive or engineered T cell-based therapies (FIGURE 1).^3—5At the 2019 Annual Meeting of the Society for Immunotherapy in Cancer, the “Primer on Tumor Immunology and Cancer Immunotherapy” session is dedicated to providing attendees with a foundation for understanding core immunology principles and highlighting the relationship of these fundamental concepts to the clinical development and application of cancer immunotherapy.⁶

“Living Drugs”: An Overview of ACTs

In adoptive cell therapy (ACT), the intrinsic anti-tumor cytotoxic activity of the host immune system, especially anti-tumor cytotoxic T lymphocytes (CTLs), is harnessed to target and eliminate the tumor cells, via adoptive transfer of tumor-associated antigen-specific CTLs, derived either from the tumor itself (TILs derived from the tumor) or peripheral blood through patient lymphocytes engineered to target tumor antigens in CAR T or engineered T cell receptor (TCR)-based cellular therapies. A remarkable feature of all types of ACTs is the potential for personalization. The fundamentals, current scope, and emerging concepts of ACT in cancer are the focus of a presentation byPATRICK HWU, MD,SITC vice president and division head, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

TIL Therapy — Modulating the TIL-Tumor Microenvironment (TME) Interaction

Seminal studies by Steven A. Rosenberg, MD, PhD, and colleagues nearly 40 years ago,⁷which demonstrated that lymphocytes extracted from freshly resected melanomas, expanded ex vivo, and infused back into the host/patients could induce high response rates in patients with metastatic melanoma, laid the foundation for tumor infiltrating lymphocytes (TIL) therapy. Solid tumors are now known to be infiltrated by many immune cells, including T and B lymphocytes, natural killer (NK) cells, dendritic cells (DCs), and macrophages. Among these, TILs are thought to be indicative of an anti-tumor immune response, a postulate supported by identification of TILs as favorable prognostic indicators in many cancers, including melanoma and breast cancer.^8,9TILs also affect treatment response; for instance, the relative abundance of CD8+ TILs predicted response to anti-PD-1 therapy in melanoma¹⁰and the presence of TILs, along with PD-L1 expression, correlated with pathologic complete response rates to neoadjuvant chemotherapy in breast cancer.¹¹

“We started utilizing [TIL therapy] first in melanoma,” Hwu, who was previously at the National Cancer Institute working with the TIL pioneer Rosenberg on some of the earliest ACT studies, “but we’re now investigating [TIL immunotherapy] in a number of other cancer types, including pancreatic, ovarian and colon cancers.” Although promising clinical data with TILs has been reported consistently for patients with metastatic melanoma, successful TIL production has also been reported for other cancers.⁵The high mutational load and high neo-antigen rates are thought to account for the significant and consistent clinical benefit of TIL therapy in patients with metastatic melanoma, whereas the heterogeneity in these key attributes, as well as key differences in the TME, may account for the variability in tumor reactivity of TILs in other solid tumors. In recent and ongoing studies, Hwu and colleagues are evaluating strategies to enhance the survival and activity of TILs in the context of the tumor microenvironment. In one such innovative approach, they have inserted the gene encoding a dominant-negative (DN) form of the transforming growth factor (TGF)-β receptor into the immune cells. Tumors, tumor-associated stromal cells and regulatory T cells (Tregs) produce large quantities of TGF-β, which acts as a key immunosuppressant in the TME.¹²Introduction of the decoy TGF-β receptor allows TGF-β depletion in the TME, with- out invoking TGF-β immunosuppressive activity, allowing TILs to mount a robust anti-tumor immune response. Speaking to the clinical utility of this approach, Hwu said, “[Using this approach], we have obtained clinical responses in metastatic melanoma patients, with disease resistant to the standard of care, including the immune checkpoint blockade agents, such as anti-PD-1 antibodies. Even if the patients had progressed after anti-PD-1 therapy, this mode of [TIL] therapy has yielded durable responses in some patients thus far.” He added that utilization of the TGF-β decoy receptor may be a feasible approach in other ACTs.

CAR T Cell Therapies — Overcoming Resistance

CAR T cell based immunotherapy relies on the recognition of antigens expressed on the tumor cell surface by the synthetic CARs transduced into autologous T cells. CARs are synthetic receptors generally constructed by fusing an antigen-specific single-chain antibody fragment (scFv) with signaling molecules of the TCR/CD3 complex, usually the CD3ζ chain. While CD19 is the most studied CAR target, the intracellular domain of the engineered CAR may also contain co-stimulatory modules, which stimulate T cell activation, proliferation and cytokine production (FIGURE 2).¹³CAR T cell therapy relies on an antibody-like—mediated binding to the tumor antigen in a major histocompatibility complex (MHC) presentation-independent manner, suggesting potential extension of antigens to non-protein molecules, such as cancer-specific glycolipids.¹⁴CAR T cell therapy has yielded promising data in hematologic malignancies, especially B-cell neoplasms.

“As the work on CD19-targted CAR T cell therapy has matured, it looks like some patients progress even after an initial response to the CAR T therapy,” Hwu said, alluding to the significant clinical challenge of resistance to CAR T cell therapy. He pointed to studies conducted by Sattva Neelapu, MD, E. John Wherry, PhD, and Crystal Mackall, MD, and others, that have helped uncover the key mechanisms of development of resistance to CAR T cell therapy — including loss of tumor antigen (e.g., loss of tumor CD19 expression) and loss of T cell “fitness” over time.^15—18

Engineered TCR-based Therapies A Look Ahead

In TCR gene therapy, a novel TCR is introduced into patient-derived T cells, by engraftment of genes encoding TCR-α and β chains, to allow for tumor antigen recognition in an MHC-dependent manner.¹⁹The potency of TCRs depends on their interaction with tumor-specific/-enriched peptide-MHC complexes; tumor-associated antigens (TAA) can be encoded by mutated genes (neoantigens) or can be derived from proteins that are overexpressed in tumors. TCRs from T cells, harboring HLA alleles matching the class in the antigen-presenting cells, recognize pMHCs, ultimately promoting the killing of cancer cells. While most current TCR therapies use MHC class I—restricted TCRs to genetically modify CD8+ T cells or bulk T cells for patient treatment, recent evidence suggests that TCR-engineered MHC class II-restricted CD4+ T cells may also have utility in cancer immunotherapy. “Many groups are now trying to develop a library of TCR genes to target various tumors, based on what tumor antigens and HLA alleles are being expressed in individual patients, to allow for transduction of the HLA-matched TCRs for adoptive T cell transfer,” Hwu said, “this approach has been already demonstrated to be successful in synovial cell sarcoma.”

Combination Immunotherapy to Tackle Challenges and Enhance Clinical Benefits

Immune checkpoint inhibitors (ICIs), which target co-inhibitory checkpoint receptors CTLA-4 or the PD-1/ PD-L1 axis, have demonstrated remarkable clinical activity in many cancers; however, despite their unprecedented success, response to ICIs is neither universal nor uniform.LEISHA EMENS, MD, PHD,SITC at-large director and professor of medicine and director of translational immunotherapy for the Women’s Cancer Research Center, UPMC Hillman Cancer Center, said, “Less than half of the patients respond to treatment with ICI monotherapy and many cancers lack the baseline immunogenicity and/or immune checkpoint pathway proteins necessary for susceptibility to immunotherapy, resulting in dramatic variations in response rates (5% to ~90%) across tumor types.” She added, “Finding a way to bring the benefit to more patients and convert non-responders to responders, finding a way to rescue patients who progress, and extending and deepening the response are all high priority goals for research. Finding ways to overcome these challenges will allow us to bring the survival benefit of immunotherapy to more patients.” Emens, who will be focusing on combination immunotherapies in her presentation, noted that these reasons underly the rationale for exploring combination immunotherapies. In addition, she stated that combinations can help harness tumor biology and integrate immune-targeted therapies with historical treatment modalities such as radiation and chemotherapy, to provide synergistic benefits to patients.

A Framework for Designing Rational Combinations with Immunotherapy Agents

Speaking to the foundational premise of combination immunotherapies, Emens said, “Many improvements can be made with immunotherapy combinations and the combination modalities should be based on the mechanism of induction of the antitumor immune response.” She elaborated on how this response has been described using the “cancer-immunity cycle,” which outlines a series of stepwise events that must be initiated, progress, and expand iteratively.²⁰She added, “if you understand what is defective in a given patient’s tumor, then you can design combinations that fill the gap and let the immune cycle be completed. If this design is predicated on underlying mechanisms and is clinically sustained, the combination can perform as a self-perpetuating cycle, where the T cell response continues until the tumor is eliminated.”

Current and emerging evidence support further development of combinations of immunotherapies, including ICIs, with other therapies or agents, as well as other immunotherapy agents in the same or different class.

For instance, the addition of pembrolizumab (Keytruda), an anti-PD-1 antibody, to standard chemotherapy with pemetrexed and a platinum-based drug resulted in significantly longer overall survival (OS; 12 month-OS, 69.2% vs 49.4%; hazard ratio [HR] for death, 0.49) and progression-free survival (PFS; 8.8 vs 4 months) than chemotherapy alone in patients with previously untreated metastatic non-squamous non— small cell lung cancer (NSCLC) withoutEGFRorALKmutations.²¹Similarly, the combination of radiation therapy, which can promote the activation of anti-tumor T cells, thereby augmenting sensitivity to subsequent immunotherapy, with CTLA-4 blockade using ipilimumab (Yervoy), improved responses in chemotherapy-refractory metastatic NSCLC, where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy.²²Further, combining two different ICIs, nivolumab (Opdivo) and ipilimumab, improved PFS, OS and overall response rates (ORRs), compared to ipilimumab alone, in patients with advanced melanoma.^23,24

Emens outlined data from combination immunotherapy studies that are coupling immunotherapy agents to novel drugs and therapies, predicated on optimizing the anti-tumor immune response based on tumor-, disease- and mechanism-specific features. Rational, mechanism-based, novel combinations can help overcome resistance, relapse or progression after immunotherapy — as in a recent study of a combination of pembrolizumab with intra-tumoral SD-101, a synthetic CpG oligo-nucleotide that stimulates Toll-like receptor 9 (TLR9), in patients with unresectable or metastatic malignant melanoma. Early data showed that this combination was well tolerated and induced immune activation at the tumor site, without additional toxicity over pembrolizumab alone.²⁵Other examples of pioneering combinations mentioned by Emens include pembrolizumab with epacadostat in patients with advanced solid tumors,²⁶nivolumab in combination with ALT-803, an IL-15 superagonist, in metastatic NSCLC²⁷and oncolytic virotherapy with talimogene laherparepvec in combination with pembrolizumab in advanced melanoma.²⁸

Emens said of her presentation, “My goal is to review the combination of immuno-therapies and their importance and provide a framework for how to think about developing innovative combinations.” Some of the key factors to consider in development of immunotherapy combinations include setting clear parameters to define the clinical “activity of a combination immunotherapy relative to the activity of either single agent in the context of the tumor type in which it is being tested”; evaluating “pharmacodynamic changes with agnostic and high-throughput systems-biology technologies”; and accounting for the effect of treatment context, drug dose, and treatment sequencing. Emens notes that while combination immuno-therapies may help expand the numbers of patients deriving benefit from immuno-therapy, it is also important to consider the potential for unexpected and/or synergistic toxicities with these combinations.

Combinations on the Horizon

The development of immunotherapeutic agents has transformed the treatment landscape of cancer across cancer types and yielded remarkable clinical benefits in responding patients, including those with advanced cancers previously thought to be intractable or difficult-to-treat. As the field matures, there is great optimism for the range of therapies in use or in development for recruiting the body’s immune system to the anti-cancer combat.

Speaking to the future of ACT, Hwu said, “I think that immune cell therapy is important and T cell therapy is very exciting. I predict that it is an area that will be growing in importance in coming years for all cancers.” He alluded to ongoing investigations that are seeking to identify biomarkers predictive of response to TIL therapy, as another avenue of growth in immunotherapy.

Emens expressed similar optimism, stating, “I believe that we will be able to make immunotherapy work for almost any tumor. If you understand the immunobiology of that specific tumor, you can design ways of eliminating it that capitalize on the anti-tumor response.” She added, “The development of combinations should consider the immunobiology of the patient’s tumor, the mechanism of each agent, and how they might interact when given together are the key to therapeutic success.”

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