Following significant back-and-forth with the FDA, interesting news seemed to slip under the radar of the biotech world as the focus is heavily on the COVID-19 pandemic: BMS/Celgene/bluebird had their BLA accepted for idecabtagene vicleucel (ide-cel; bb2121) their autologous B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T‑cell immunotherapy. If approved in 2021, ide-cel will be the 4th CAR-T immunotherapy product approved by the FDA, following Novartis’s Kymriah and Kite/Gilead’s Yescarta in 2017 and Tecartus in July of 2020. While certainly exciting news in its own right, this approval, the first of its kind for multiple myeloma (MM), may well be a weathervane indicating where the biotech winds are blowing. As late stage immunotherapies inch closer to approval and new methods are constantly pushing the cutting edge, the 2020s promise to be an exciting decade for immunotherapy research and clinical results.
As a professional recruiter in the immuno-oncology market, I work with companies developing novel and fascinating methods to combat cancer every day, and am exposed to the diversity of approaches different biotechs take toward these same ends. In this article, I’ll look at some of the most innovative immunotherapies in development now, and the biotechs behind them, each hoping they have the answer to cancer.
Allogeneic CAR-T
As exciting as the cell therapy revolution in biotech going on now is, the field itself may only be in its nascent stages. The current crop of CAR-T therapies, both those already approved and those just about to cross the finish line, are all autologous therapies: each therapy is patient-specific, and requires significant production time before use. The patient’s T-cells need to be collected from their blood, transported to an approved centralized manufacturing facility, and genetically modified to express the cancer-targeting Chimeric Antigen Receptor, then infused back into the patient to act as a therapeutic. This process can take 3-4 weeks from initial extraction to reintroduction, and as many patients are in their 2nd or 3rd relapse before treatment, this timeframe can very literally be deadly. Moreover, the time and work required to produce the CAR-T cells for each patient is reflected in the cost of the medications: $475,000 for Kymriah and $373,000 for Yescarta.
In terms of the cells themselves, autologous therapeutics by necessity have to use very unhealthy and “depleted” immune cells: those of the very sick cancer patient they’re taken from, and will be given back to. For patients like this, autologous cell therapy may not even be an option. Finally, there can be very significant side effects from these medications, including autoimmune cytokine release syndrome (CRS) and neurological toxicity. CAR-T 1.0 has had some fantastic results, for both patients and the immuno-oncology community, but there are certainly areas for improvement.
Enter Allogeneic CAR-T Therapy: off-the-shelf, healthy, instantly available, universal CAR-T treatments. The idea is to be able to mass produce non-immunogenic CAR-Ts either from healthy donors or from stem cells. From the stem cell approach, these cells will be differentiated into T-cells and genetically modified to express CARs. They will also be stripped of immune markers to prevent immunogenicity and resultant autoimmune responses, allowing them to be delivered to any patient who needs them.
Of course, all of this is far more easily said than done. Even starting from healthy donor or stem cells, removing all immune markers is a monumental task, with far more false starts and headscratchers than breakthroughs. Still, many companies are working tirelessly in this endeavor. Servier/Cellectis, in collaboration with Allogene, are farthest along, with their UCART19 program in Phase 1 clinical trials. The program has seen the usual symptoms (cytokine release storms, graft vs host disease, neurotoxicity), but at manageable enough levels to inspire optimism. Other companies, such as Kite/Gilead and North Carolina-based Precision Bioscience are also entering the clinic with their allogeneic products, and new companies are popping up in this space on what seems like a monthly basis. Still, the field is both relatively new and absolutely complex, so only time will tell if the dream of a universally available, off-the-shelf cancer treatment can be a real possibility for patients that need it.
Cancer Vaccines
While CAR-T has been the posterchild of the new wave of immunotherapies, other fascinating approaches are also being developed that use the immune system to attack tumors in other ways. One such method is the use of cancer vaccines, which stimulate the immune system to attack cancer-specific surface markers, or antigens. Just as in cell therapy, two primary approaches are being taken to cancer vaccines, autologous and allogeneic.
Autologous cancer vaccines, known as personalized cancer vaccines, use the patient’s specific tumor samples to create a vaccine against the antigens expressed on their tumors, and make up the majority of cancer vaccines currently in clinical trials. Allogeneic cancer vaccines are off-the-shelf vaccines, aimed at targeting tumor-specific antigens common to specific cancer types and applicable to a large cohort of patients. In technical terminology, these vaccines go after neoantigens, novel tumor-specific antigens that appear due to mutations in tumor development, and are not found on healthy cells.
While there is only one approved non-viral/non-bacteria based cancer vaccine in the US, Dendreon’s Provenge for prostate cancer, approved in 2010, advances in bioinformatics and whole-exome sequencing to find novel neoantigens have led to the re-emergence of cancer vaccines as a significant area of research and development. There are currently 387 cancer vaccine clinical trials ongoing, second only to cell therapy (582 active clinical trials) within the IO world, attempting to overcome challenges such as tumor-associated immunosuppression, heterogeneous and constantly mutating tumors, and the weakened natural immune response of patients who have undergone chemo or radiotherapy.
While neoantigen-based personalized cancer vaccine company Neon Therapeutics’ recent troubles, complete with a massive fall in stock value, significant layoffs, and a (ultimately successful) buyout by BioNTech, may cast a cloud over the field, others continue undaunted. Cambridge-based Glyde Bio is targeting a surprisingly unexplored area of IO, tumor-specific glycan antigens, while another biotech, Cambridge-based Elicio Therapeutics, are combining cell therapy with a unique amphiphilic cancer vaccine to get the best of both worlds. While these companies are either pre-clinical or just entering the clinic, there is optimism that the lessons learned from previous lackluster results will inspire a renaissance in the cancer vaccine world, and lead to effective, safe, and groundbreaking therapies.
Microbiome
Although cell therapy and cancer vaccines have a significant history behind them, one wholly novel and rapidly emerging field of IO study is the microbiome, or the relationship between the bacterial colonies that live in the human gut (the microbiota) and many types of diseases, including cancer. Mounting evidence suggests that the microbiota has a very significant impact on the immune system, such as the commonly observed phenomenon of “germ-free” mice (mice without gut bacteria) having severely lowered levels of immune response. Others have noted the impact of the microbiota on immune checkpoint inhibitors (tumor associated immune suppression, common targets for anti-tumor immune stimulation), with germ-free mice demonstrating markedly lower success in anti-immune checkpoint inhibitor therapies. Furthermore, direct evidence exists that translocation of certain gut bacteria had an “immune priming” effect, and increased T-cell anti-tumor response.
While the preclinical evidence for the impact of gut bacteria on cancer immunotherapy is exciting, the clinical evidence is so far minimal. A handful of clinical trials in the “oncobacterial” space are ongoing, with Cambridge-based Evelo Bioscience leading the way with three trials in Phase I/II. So far, data has been encouraging, demonstrating increased immune response and delayed tumor growth, but it’s still early days. Much more research and human trials need to be conducted, but it should go without saying that the “good bug” space is one to watch in the coming decade.
Small Molecules – What of the Old Guard?
While novel therapeutic modalities such as cell therapies, cancer vaccines, and microbiome research are shaking up both the scientific and investment communities, one modality that is sometimes overlooked in the buzz, but not in the clinic, are small molecule therapeutics. These small synthesized chemical compounds make up the majority of oncology drugs, both on the market and in human trials. In many ways, they have significant advantages over “sexier” oncology and IO therapies: small molecules are easier to design, easier to test, and far easier to manufacture than cell therapies, resulting in far lower costs. They’re able to penetrate cells and go after intracellular targets, while larger biologic and cell-based therapies can only target extracellular antigens. Dosing is far easier to control, and autoimmune responses are relatively minimal.
Moreover, small molecules can be used to directly attack tumors by going after cancer growth and survival pathways, as well as being used as immuno-stimulatory agents by targeting pathways in immune cells, allowing for multiple mechanisms to fight cancer. And while many IO therapies, including CAR-T therapies, have difficulty going after solid tumors, small molecules are able to penetrate the tumor microenvironment and prove effective, both in killing cancer cells and making tumors more susceptible to immune attack.
That said, there are causes for concern with small molecules as well, namely toxicity in regards to both off-target effects (small molecules can’t “hone in” as well as biologics and cell therapies, and can often hit healthy targets they’re not supposed to) and immune response against them, as they’re still foreign agents entering the body. That said, cell therapies suffer from similar issues.
Thus, with so many unique benefits and few unique drawbacks, the question can’t help but be begged: why bother with costly, cumbersome next-gen immunotherapies when, on the face of it, small molecules are superior in so many ways? Why devote countless billions in dollars and highly specialized knowledge to develop new therapeutic modalities when the old guard is still the standard?
To answer that cliffhanger of a question with billions of dollars and countless lives riding on it, it’s because cancer is a hydra that would make Hercules himself turn and run, and requires every answer we can dream up and prove in the lab to be able to cut off all of its heads and defeat it for good. Different therapies target different antigens, and attack cancers in ways that other therapies can’t. Combination treatments with small molecules and different immune therapies mentioned here aim to tackle tumors from multiple angles, and each make up for the shortfalls and limitations of the others. While small molecules have many upsides, they can’t target all types of cancers, and can result in relapse, while immune therapies such as CAR-T, bispecific antibodies and ADCs can be fine-tuned to treat otherwise untreatable cancers, and can be given to relapsed patients when small molecules can’t.
Cancer isn’t an either/or dilemma, and to think that any one modality or one drug is the defining cure is foolish. Rather, new immune therapies that chip away at defined (and in some cases, not yet defined) cancer weaknesses, in combination with proven drugs and the highest clinical standards of care, will come to define cancer treatment in the 2020s. Hopefully it will be this synthesis taking shape between traditional oncology and novel immuno-oncology that will prove, finally, to be the answer to cancer.
Sources
Journal of Clinical Oncology 2019 37:15_suppl, e14241-e14241
