Tumors aren’t foreign invaders; they are of the body—a rogue collective of mutant cells that rebel, morphing from symbiotic into selfish, devouring the body they inhabit in order to grow, spread, and colonize new and distant organs.

However, despite the insurgency against the body, tumor cells retain remnants of their former lives: their mosaical coats of molecules and antigens still read “home team.” Like Trojan horses, they slip past the very defense system that should destroy them, even hijack it, at times. Unlike traditional treatments like chemotherapy and radiation, immunotherapy ramps up or redirects the immune system in order to seek out and destroy tumor cells. The most publicized immunotherapies of late include CAR T cell therapy and checkpoint inhibitors.

Crafting living medicine

A rapidly emerging approach, adoptive cell transfer (ACT) uses modified versions of patients’ own immune cells to fight their cancer. Among the several in development and testing, CAR T-cell therapy shows the most promise thus far. Dubbed the Advancement of 2018 by the American Society of Clinical Oncology, CAR T-cell therapy tweaks T cells, endowing them with the ability to see through cancer’s disguise and identify these cells as non-self. By collecting T cells from a patient’s blood and genetically engineering them to express synthetic chimeric antigen receptors (CARs) at the surface, they become capable of recognizing and attaching to specific antigens on the tumors and can orchestrate an immune response that spells destruction.

Scientific efforts focus on getting T cells to expand and survive longer once inside our bodies. Recently, further advances have enabled scientists to also cut down on the time it takes to generate a batch of CAR T-cells, from several weeks to less than one week.

Checkmate

The immune system searches for pathogens to destroy. When it becomes indiscriminate and attacks cells that should be there, autoimmune disease arises. As such, powerful checkpoints are in place to prevent just such an occurrence. Unfortunately, these checkpoints can be a hindrance in recruiting immune cells to eliminate cancer cells. “Checkpoints” refer to specific molecules on immune cells that can trigger (or prevent) an immune response.

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Some cancers evolved ways to express certain “checkpoint” molecules in abundance, thus stifling an immune system that would otherwise be able to fight off the cancer (keep in mind that our immune system gets rid of cancer cells all of the time—it only becomes a problem when it becomes overrun). Monoclonal antibody-based medications, checkpoint inhibitors, are altering the course of many types of cancer treatments. Current medications target surface receptors, CTLA4, PD-1 or its suppressor, PDL-1. By blocking the activity of these molecules on the T-cell surface, the immune system is able to attack the cancer. These drugs are used alone or in combination with other medications.

Immunotherapy encompasses far more than described here, including other monoclonal antibodies (like herceptin), cytokines (like interferon), and vaccines (still in the early stages of development). Both established and developing treatment strategies depend on basic science techniques that have become more specific, more efficient, and more powerful with each iteration. “Humanized” mice, antibodies, gene-editing, gene transfer, cell imaging, are all invaluable in leading the charge to develop cutting-edge drugs and treatments that are fast joining the ranks of the canonical triad of surgical resection, chemotherapy, and radiation.

Of (humanized) mice and men

Clinical responses to certain immunotherapies are promising, and in some cases, downright miraculous. But these benefits still only apply to a minority of patients and only with respect to certain “susceptible” cancers. Predictive clinical models are required to drive drug development and minimize clinical trial failure. Of the engineered mouse models used in cancer research, most suffer from a looming caveat: they have an intact mouse immune system.

Enter the “humanized” (HIS) mouse. These animals generate functional human immune systems infusing the preclinical animal model with greater relevance and predictive value in assessing potential new therapies. Popular models use the nonobese diabetic severe combined immunodeficiency (NOD scid) gamma (NSG) transgenic mouse line, endowed with a human immune system using either CD34+ hematopoietic stem cells or peripheral blood lymphocytes (PBL).

These lines support the growth of patient tumors in the context of a human-like immune system in the compact package of a mouse. Patient-derived xenograft (PDX) models allow for the “AVATAR” approach whereby a patient’s tumor is grafted into immunodeficient mice allowing for growth and molecular characterization and evaluation of treatment efficacy for that particular tumor. Compared to conventional xenografts, these models recapitulate tumor heterogeneity, gene expression profiles, and response to chemotherapy. The potential for facilitating personalized medicine is there, however, there are still significant obstacles, such as the timeline length for generating such mice (2-12 months) and difficulty assessing metastases.

HIS models were instrumental in propelling CAR T cell therapy forward. Following several preclinical studies in these mice, the FDA approved the treatment for B-cell acute lymphoblastic leukemia in 2017. However, while HIS mice encapsulate many aspects of the disease and treatment, they fail to reproduce the serious, sometimes deadly side effects of the therapy such as the “cytokine storm” and neurotoxicity. It is the hope that more sophisticated, HIS models will help to identify off-target effects and create safer treatments.

These mice continue to be used to figure out how to generate CARs to target other types of cancers, to test the antitumor efficacy of different CAR designs, such as those that contain immune-enhancing costimulatory domains, and in combination therapies that utilize both CAR T cells and checkpoint inhibitors. Other lines of inquiry include overcoming the immunosuppressive properties of the tumor microenvironment.

Re-engineering immune cells, re-evaluating cancer cells

Gene-editing technologies also continue to metamorphose, enabling immunotherapies that should work in theory to actually function in preclinical and clinical settings.

Once notoriously difficult to manipulate, natural killer (NK) cells can now be genetically engineered through electroporation of cGMP-compliant mRNA (opening the door to weaponizing NK cells for ACT). Meanwhile, mixing cells with mRNA nanocarriers prior to transient transfection can permanently reprogram cells. Referred to as the “hit and run” approach, CAR T cells can be transformed into even more aggressive and longer-lasting memory T cells by way of foxo1 mRNA nanocarriers.

Redesigned CAR T-cells can now attack T cell malignancies, too—a previously impossible schema due to a surface protein (CD7) shared by both cancerous and normal T cells. Targeting this protein would result in destruction of cancer cells and the CAR T cells. Scientists now show that by deleting CD7 from healthy T cells with CRISPR-Cas9 technology, cell “fratricide” is prevented with only the cancerous cells getting killed.

Since the healthy T-cells come from donors, researchers also used CRISPR to delete a T cell receptor subunit that detects healthy foreign tissue, preventing the potentially deadly, graft-vs-host disease. Newer versions of CAR T cells move more cancers into the realm of the treatable, but also circumvent the need to find a matched donor. “Shelf-ready” CAR T cells can be generated and available without delay for patients. These cells are currently being scaled up for clinical trials.

Progress, but a long way to go

Immunotherapy isn’t just burgeoning; it’s resounding. But as long as cancer (and the treatments) continues to instill dread, much work remains.

Many areas are still ripe for exploration and refinement. For example, of the 20 odd different checkpoints out there, only a few are being actively exploited. And while these drugs receive much publicity, they are the answers for only a few cancers. In fact, they can actually exacerbate other T cell derived tumors or cause hyperprogression of cancer in patients with particular mutations. There is also the matter of the delicate balance between engineering the maximal immune response against tumor cells and crossing the tripline into autoimmune destruction, highlighting the need for profiling individual patient cancers and genomes for the best outcome.

Maintaining the balance between checkpoint suppression and activation is one area aided by more sensitive techniques such as multiplex immunoassay platforms and ELISAs, validated antibodies, and powerful imaging reagents. Impetus at the basic science level can lead to exponential consequences for preclinical and clinical applications.

The ultimate goal of immunotherapy is to craft personalized living medicine that empowers the body to eradicate cancer on its own with minimal side effects. While that is a tall order, the beginnings of such options are fast seeping into the cancer treatment regime. Science fiction no more; immunotherapy has arrived.

The Takeaway

  • Immunotherapy kills cancer by recruiting or exploiting the immune system. Killing cancer in the context of the immune system prevents rogue cancer cells from being left behind, as can happen with other traditional treatments like chemotherapy or radiation.
  • Types of immunotherapy include adoptive cell therapy, checkpoint inhibitors, monoclonal antibodies, cytokines, and cancer vaccines.
  • CAR T cell therapy (a type of adoptive cell therapy) is incredibly promising, but only approved for blood cancers. Many solid tumors have multiple mutations that make it difficult to identify the one target driving tumor growth.
  • Checkpoint inhibitors are an antibody-based drug therapy that prevent cancer cells from hiding from the immune system under a “cloak” of molecules that identify them as belonging in the body. While only a few are currently being exploited, many other checkpoints with potentially greater potency are emerging.
  • Humanized mouse models are endowed with a human immune system that more accurately depicts the interactions between grafted tumors and immune response to treatment. However, these models do not demonstrate the same, sometimes deadly, side effects seen in patients.
  • Cancer immunotherapy yields exciting results, but only for a minority of patients. Preclinical models, advances in gene-editing (like CRISPR), more sensitive assays and efficient reagents, and unearthing and characterizing predictive biomarkers will be instrumental in propelling the field forward.

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