The menu can be confusing, and it’s changing.1 It has changed dramatically in the course of the years during which this book was researched and written, and it will continue to change. But what can be helpful to keep in mind is that what most (not all) immunotherapies have in common is the T cell.
IL-2 grows and energizes them, adoptive T cell therapy grows and farms them, checkpoint inhibitors unleash them, vaccines inform and activate them, and CAR-T is them, the robocop version. Immune response is complex. There are many players involved, many are surely undiscovered, and only a few are understood. But in terms of cancer treatment, the goal is simple: get cancer-killing cells to do their job as quickly and selectively as possible.
Anything that accomplishes that is an immunotherapy.
That includes a class of immunotherapies that simply works as a universal adaptor on the molecular scale, chaining T cells (or natural killer cells) to the cancer cells with protein handcuffs. Called bispecific antibodies, or BsAbs, these bioengineering marvels are like an aggressive matchmaker at a high school dance. There’s currently hope that such an approach will be more effective after a checkpoint inhibitor like anti-PD-1 / PD-L1 turns on the lights, revealing to the T cell that its dance partner is cancer.2 Currently the CD3 bispecifics are particularly promising. These bind to the cytotoxic T cell–stimulating CD3 site on the T cell and various antigen targets on tumor cells.3 Two such drugs have been approved by the FDA (blinatumomab, Amgen) and for use in Europe (catumaxomab, Trion Pharma). It’s reported that more than sixty such drugs are in preclinical phase and thirty are in clinical trials, the majority of which have cancer as the target.
We are living in the checkpoint inhibitor phase of cancer immunology, or perhaps the second half of that phase (CTLA-4 was the pioneer, PD-1 / PD-L1 is the present), and already researchers speculate that we’ve plucked the low hanging fruit. This is the era of the combinations.
Combinations
In addition to combining existing checkpoint inhibitors with one another4 (Ipi + a PD-1 / PD-L1), some combinations include checkpoint inhibitors plus:
chemotherapy; radiation therapy; T cell agonist cytokines such as IL-2; new customized vaccines; and, in a technological twist reminiscent of Coley’s Toxins, inoculated bacterium such as listeria or small molecules. This is a far from complete list.
There are more potential checkpoints being discovered, as well as numerous new therapeutic approaches to induce tumors that are not very immunogenic (visible to the immune system), to express unique antigens, or in some other way make those cancers viable immune system targets.
Anything that makes cancer more visible as an immune target is a potential partner for drugs that unleash immune cells to attack those targets.
The list of combinations being tried as of July 2020 is reported to run into the thousands.
A “cellular therapy” is any cancer treatment that uses a whole living cell as the “drug” (rather than just a folded protein or other molecule as the therapeutic agent). That includes adoptive T cell therapy, a method that essentially farms T cells, grows out the ones effective against cancer, and transfers them back to the patient. Notable advances to this method were led early on by pioneering work from Fred Hutchinson Cancer Research Center’s Phil Greenberg as well as work by Dr. Steven Rosenberg’s colleagues at the National Cancer Institute, which was one of the first centers to push this technique into the clinic and which has continued to grind out progress in this approach for decades. In June 2018 Rosenberg’s team published results of a successful adoptive T cell transfer therapy that saved the life of a forty-nine-year-old Florida woman with stage 4 breast cancer and large tumors throughout her body. As of July 2020, Judy Perkins had no evidence of the disease, after receiving an infusion of some 90 billion of her own T cells.5
CAR-T is (at present) the best-known cellular therapy and one of the most exciting to watch. It works. It’s shown to be hugely effective against those cancers the CAR can be reengineered to target. Right now that’s a limited subset of cancers, mostly blood-borne cancers. Various new approaches currently under way attempt to make that list of applicable cancers bigger, expanding the settings in which patients may safely receive this treatment while shrinking the price tag for what is now an entirely bespoke drug.6 Advances in gene editing and insertion are leading to numerous new groups pursuing their own CARs across the world (especially in China).
It is now possible to insert several genes at a time into a T cell, which may lead to CARs with multiple protein targets. Ongoing research suggests it may also be possible to edit the T cell so that it has built-in defenses against the tumor microenvironment. CAR-T is also being tested in combination with checkpoint inhibitors and other immunotherapies.
Vaccines
The vaccines we were building even ten years ago had the right idea, but they were based on biology that was poorly understood and technology insufficient to executing these approaches effectively. Now the tech has caught up to the concept.7 The buzzword now is “personalized cancer vaccines.” Dan Chen explained it this way:
“We can take samples from the patient. We can sequence the whole genome really quickly, both the patient’s genome and the tumor genome. The computer can take this totally ginormous data set and go boom boom boom, OK, here it is, here’s your twenty top sequences. And we have a way to make a drug around those top sequences really fast. Will it work? We don’t know. But the signs are really, really good.”
Older vaccines are also now getting second looks following the discovery of checkpoint inhibitors, and our new understanding of how tumors manipulate, down-regulate, and suppress normal immune response. Researchers are currently reevaluating previously shelved cancer vaccines (such as GVAX) in the new light of checkpoint inhabitation.
The Tumor Microenvironment and Other Targets
Tumors create a sort of microatmosphere, called the tumor microenvironment, which they poison with a smog of enzymes and immune inhibitors that choke out or shut down T cells. That environment surrounds the thousands of proteins a tumor expresses on its cell surfaces.
We are already familiar with some checkpoint inhibitors, but this is the tip of the iceberg. There are perhaps fifty potential targets to attack in this environment. Researchers are also exploring the arena of agonists, which stimulate (rather than inhibit) immune cells. Interesting and exciting research is ongoing on targets such as CD-27, CD40, GITR, ICOS, and others, although it’s premature to speculate much on OX40 until more clinical data is available.8 Cytokines are also the subject of a great deal of research and academic activity; in addition to the revisiting of the importance of IL-2, IL-15 is reported to be a reasonable candidate for future cancer immunotherapies. Additionally, there is renewed interest in the role played by other immune cells in T cell priming and activation, and how they might contribute to control of the immune-suppressive factors in the tumor microenvironment.
The role of macrophages, dendritic cells, natural killer cells, and others previously assumed to only be agents of innate immunity is a fast-moving research front, as are new findings about the role played by the microbiome of the gut in immune modulation, signal induction inhibitors (such as BRAF and MEK inhibitors), as well as microbiota alteration, activation of antigen presenting cells, targeting of cancer stem cells on tumor strata, and factors including nutrition, exercise, and even sunlight.
One of the takeaways from this list may be the simple fact that immunology is complicated and involves a lot of players. Basic scientific research is required to better understand these players and to understand them in regards to cancer. Immune response is a complex conversation. We have only started to learn how to listen.
An exciting and somewhat separate approach within immunotherapy uses viruses to selectively sicken and kill tumor cells without harming normal body cells. The result is essentially a disease for your disease—a disease that makes only cancer sick. As of this writing the only FDA approved version of this therapy, called talimogene laherparepvec (brand name Imlygic), or T-Vec, uses a genetically modified version of the herpes virus to infect melanoma cancer cells. The melanoma is reprogrammed to create immune-stimulating proteins and more of the cancer-infecting virus; in time the melanoma cell bursts, spewing telltale tumor antigens that alert the immune system to join the attack. This approach (in combination) is showing greater success against some tumors than checkpoint inhibitors alone and is being investigated as a means to turn cold tumors (which for whatever reason repress or avoid the attentions of the immune system) into hot tumors.
Biomarkers
Most cancer immunologists point to the problem of so many new therapeutic options for patients who can ill afford the time or resources of the wrong approach. Tests are needed, capable of categorizing both a patient’s immune system and the specifics of their cancer, in order to help clinicians of the future determine the most effective therapy. Some clinicians and researchers are now calling for an evaluation of a patient’s “immunoscore” as an important early step in treating cancer.