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Tuesday, January 3, 2017

A Look At Cancer Immunotherapy And Some Key Players In 2017

Cancer immunotherapy, exploiting the abilities of the immune system to treat cancer, is fast becoming the standard of care for many malignancies and offers the best hope for curing patients of their disease. For biotech investors, the prospect of curing cancer has led to an abundance of opportunities as more and more companies enter the space. There is even an ETF dedicated to cancer immunotherapy (NASDAQ: CNCR).

While the ultimate goal is a cure, even turning cancer into a chronic disease, as opposed to a death sentence, would be a major step forward for patients. We are in an exciting time for cancer treatment because this dream is becoming closer to reality. I believe that advances in cancer immunotherapy will result in a change in the standard of care for cancer patients much in the same way that occurred for patients with HIV/AIDS and hepatitis C over the past 10-15 years.

For example, AIDS was once considered an untreatable condition, but new treatments that combine several agents to attack HIV through multiple mechanisms have turned what was once a death sentence into a chronic disease for some patients.

Similarly, hepatitis C was once considered a chronic, life-long illness that could eventually lead to death from cirrhosis and/or liver cancer. However, with the recent approval of some new therapies (Sovaldi® and Harvoni® from Gilead Sciences; Viekira® from AbbVie), close to 100% of patients with hepatitis C are being cured of the disease following 8-12 weeks of treatment with minimal side effects.

I believe it’s only a matter of time before cancer follows the same progression as both HIV/AIDS and hepatitis C, and immunotherapy treatments will be at the center of the treatment paradigm. For this reason, I’ve put together an introduction to cancer immunotherapy so investors can be more comfortable with the field, focusing on two of the most promising areas, along with the names of a few companies that are focused on developing these promising therapies.

A Quick Introduction To Cancer Immunotherapy

The term ‘cancer immunotherapy’ is an all-encompassing expression that refers to the use of the immune system, and all of its inherent abilities, to treat cancer. In 1909, Paul Ehrlich first postulated that cancerous cells continuously arise in our bodies and that the immune system eliminates these cells before tumors can take hold, in a process referred to as immune surveillance. While controversial, multiple lines of experimental evidence have shown the ability of the immune system to control tumor outgrowth (1). 

For reasons that are not fully understood, cancer cells are able to evade immune recognition and subsequent destruction. This process typically involves suppression of the natural immune response, induction of tolerance, and disruption of T cell signaling. The ultimate goal of cancer immunotherapy is to ‘re-ignite’ the immune system’s response to a neoplasm, which is currently attempted through a number of different mechanisms including the use of exogenously administered cytokines, adoptive cellular therapy, vaccines, and immune checkpoint blockade. 

For the purposes of this article, I will focus on augmenting immune checkpoints and adoptive cellular therapy, as these have shown the greatest clinical efficacy and are the focus of some investable ideas in the sector.

Immune Checkpoint Blockade

The immune system contains a number of inhibitory pathways (immune checkpoints) that are necessary to prevent an uncontrolled immune response as well as to control its severity and length (2). While cancer cells typically express a number of neo-antigens that would normally be recognized by the immune system as foreign and warrant the cells elimination, cancer cells also express ligands that bind to and exploit these immune checkpoints to induce tolerance. The following figure shows the number of pathways that are involved in controlling the activation of tumor infiltrating lymphocytes (TILs) by antigen presenting cells (APC) or cancer cells. Because these checkpoints involve the binding of ligands to receptors, these pathways can be easily augmented through the use of monoclonal antibodies.

- CTLA-4

The first target for checkpoint blockade using a monoclonal antibody was CTLA-4, an inhibitory receptor that is induced in activated T cells to ultimately stop proliferation (3). Anti-CTLA-4 antibodies showed anti-tumor activity in a number of preclinical models (4), and ipilimumab (Yervoy®; Bristol-Myers Squibb), a humanized anti-CTLA-4 monoclonal antibody, was approved by the U.S. FDA for the treatment of melanoma based on increased overall survival in Phase 3 clinical trials (5).

Unfortunately, the use of ipilimumab has been met with some challenges. As would be expected based upon the results seen with CTLA-4 knockout mice, which develop lymphoproliferative disorders by four weeks of age (6), a sizeable percentage of patients treated with ipilimumab experience immune-related adverse events (7). Also, because checkpoint blockade targets the immune system and not the cancer itself, treatment effects can take a long time to manifest, making efficacy assessments challenging using response criteria that were developed based on the use of more rapid-acting chemotherapeutic agents (8). However, the initial results seen with ipilimumab, particularly since it was the first agent to show a survival benefit in patients with metastatic melanoma, hastened the search for more effective and less toxic checkpoint inhibitors.

- PD-1

In contrast to CTLA-4, which has a central role in regulating T cell activation, PD-1 is involved in the regulation of T cell activity in peripheral tissues at the time of an inflammatory response through interaction with its two ligands, PD-L1 and PD-L2 (9). The two ligands are expressed on the surface of a number of different cancer cell types (10), while PD-1 is expressed on a large proportion of TILs (11). This expression pattern of PD-1 and its ligands, along with the relatively mild phenotypes of PD-1, PD-L1, and PD-L2 knockout mice (compared to CTLA-4 knockout mice), suggested that interruption of PD-1 signaling could have good clinical activity with decreased immune toxicity. 

Nivolumab (Opdivo®; Bristol-Myers Squibb) and pembrolizumab (Keytruda®; Merck) are both anti-PD-1 antibodies while atezolizumab (Tecentriq®; Roche) is an anti-PD-L1 antibody. The FDA has approved each of those antibodies for at least two indications based on an increase in objective response rates (ORR) compared to the standard of care in registration-quality clinical trials. The following chart shows the ORRs for the three antibodies for their currently approved indications, as well as the ORR for the comparator treatment (if available) from the registration trials:

In addition to CTLA-4 and PD-1, there exist a number of other checkpoint receptors that are currently being investigated, including:

LAG-3 - Lymphocyte-activation gene 3 (LAG-3) is expressed on activated T cells, Treg cells, B cells, and dendritic cells (12). Interestingly, co-expression of PD-1 and LAG-3 occurs on exhausted T cells, thus blockade of both receptors together results in additive therapeutic activities in preclinical models (13).

TIM-3 - T-cell membrane protein 3 (TIM-3) serves to blunt T cell effector function and induces apoptosis of T cells (14). TIM-3 blockade has shown activity in preclinical models of colon cancer, melanoma, and sarcoma, in particular when combined with PD-1 blockade (15, 16).

Combination Therapy - The Future of Cancer Treatment

Due to the heterogeneity of tumors and the complexities surrounding host immune responses, it is assumed that combination immunotherapy is going to be the most effective means of treating cancer patients. In addition, only a subset of patients respond to monotherapy with anti-CTLA-4 or anti-PD-(L)1 therapy. Based on the very promising activity of anti-PD-(L)1 antibodies, and manageable side effects obtained with targeting the PD-1 pathway, blockade of the PD-1 signaling pathway is likely to be the cornerstone of most combination therapies. The following chart, obtained from Vanessa M. Lucey, Ph.D., shows the vast number of combination studies currently underway using PD-1 blockade in an array of different cancer types.

A few examples of the types of combination therapies currently being investigated and additional pathways that could be tested along with PD-(L)1 blockade include:

- Combination Checkpoint Blockade

Since PD-1 and CTLA-4 affect different signaling pathways, the combination of anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) was tested in metastatic melanoma patients. Compared to ipilimumab alone (ORR = 19%) or nivolumab alone (ORR = 44%), the combination of nivolumab and ipilimumab was superior (ORR = 58%), albeit with an increase of Grade 3 or 4 treatment-related adverse events (17).

- Immunostimulatory Antibodies

In contrast to checkpoint proteins, which serve to down regulate the immune response, there also exist a number of receptors designed to stimulate an immune response. Thus, instead of blocking the interaction between ligand and receptor, as is the case with checkpoint inhibitor antibodies, the goal of immunostimulatory antibodies is to serve as agonists and activate the receptors. Immunostimulatory antibodies are being developed by some different companies, with a few examples of the receptors including:

4-1BB - 4-1BB (CD137) is expressed on the surface of primed T cells and natural killer cells and has been shown to promote T cell activation, growth, and survival along with potent anti-tumor responses in various preclinical models (18). Urelumab is an anti-4-1BB antibody in development by Bristol-Myers Squibb that results in systemic activation of 4-1BB signaling, and while it has shown anti-cancer activity in a Phase 1 clinical trial (19), another Phase 1 trial in melanoma patients had to be discontinued due to hepatotoxicity (20), most likely brought about by the systemic activation of the receptor. Thus, targeted activation of 4-1BB in the tumor microenvironment will likely be required to safely exploit this pathway.

OX40 - OX40 is a costimulatory receptor found on T cells, and its activation promotes T cell survival, proliferation, and cytokine production (21). OX40 agonists have shown activity in some preclinical models (22), and a Phase 1 clinical trial with an OX40 agonistic antibody had an acceptable toxicity profile while 12 of 30 patients showed regression of at least one metastatic lesion (23).

GITR - Glucocorticoid-induced TNFR-related protein (GITR) is upregulated in activated T cells and activation of GITR augments T cell proliferation, cytokine production, and resistance to Treg-mediated suppression (24). Agonistic anti-GITR antibodies result in anti-tumor responses in preclinical models of colorectal cancer (25) and melanoma (26).

CD40 - CD40 is expressed on dendritic cells, macrophages, monocytes, and B cells along with various types of malignant cells including melanoma, lymphoma, and leukemia (27), CD40 ligand (CD40L) is expressed by CD4+ T cells, which allows for antigen presenting cells to activate T cells. Agonistic antibodies that target CD40 are being developed, with some showing strong antitumor activity when combined with chemotherapy in patients with pancreatic cancer (28).

- Radiation and Chemotherapy

Radiation is incorporated into the treatment regimen for a number of tumor types, including glioblastoma and breast cancer. While radiation treatment is known to activate CD8+ T cells (29), it can also increase expression of PD-L1 (30), which may reduce any radiation-induced anti-tumor effects. This also serves as a rationale for combining radiation therapy with PD-1 pathway blockade.

Preclinical models suggest that the therapeutic response to some chemotherapy agents (e.g., anthracyclines) may depend on proper immune activation through interferon-gamma signaling, which can also induce PD-L1 expression (31). This would suggest that some chemotherapy agents may work in conjunction with PD-1 pathway blockade. However, additional studies will be needed to elucidate which chemotherapy agents and what doses could be utilized with anti-PD-(L)1 agents.

While there are additional pathways that are being exploited alongside PD-(L)1 pathway blockade, the point is that monotherapy, particularly for solid tumors, is unlikely to lead to sustained anti-cancer responses in a majority of patients. However, due to the relatively manageable side effects of most immunotherapy treatments, combinations of various therapeutic options that includes checkpoint blockade could potentially lead to meaningful responses for a large proportion of cancer patients.

The Excitement Over CAR-T

In addition to checkpoint blockade, perhaps no other cancer immunotherapy approach has generated as much excitement as that involving the genetic manipulation of T cells with chimeric antigen receptors (CAR). First-generation CAR-T cells consist of a single-chain variable fragment (scFv) derived from the variable heavy and light chains of an antibody that can target an extracellular antigen along with the CD3ζ chain, which is the signaling domain of the TCR complex (32). Second-generation CARs add an additional co-stimulatory domain (activation signal 2) consisting of CD28 or 4-1BB (33, 34). Third generation CARs have two co-stimulatory domains. A graphical depiction of CARs is shown in the following image.

CAR-T cells are produced by extracting T cells from a patient and genetically engineering them to express the CAR, typically through the use of a viral vector. The CAR-T cells are then expanded in vitro before being readministered to the patient. Since the cells are autologous, there is little risk of rejection. Following readministration, the CAR-T cells expand in number in response to the antigen that is targeted, typically a protein on the cell surface that is uniquely expressed by cancer cells.

Early results with CAR-T therapy in different blood cancers have been highly encouraging; however, there is a unique set of side effects that must be managed that results from the treatment, some of which can potentially be fatal. Just as other T cells do, CAR-T cells release cytokines when activated. However, the potency of the response by CAR-T cells can result in a massive influx of cytokines in the bloodstream, resulting in dangerously high fevers and dramatic drops in blood pressure, which is termed cytokine-release syndrome (CRS). The use of steroids and anti-IL-6 antibodies can be used to counteract the effects of CRS, although even with supportive care some patients have died as a consequence of CAR-T treatment.

- CD19

Thus far, all advanced clinical studies of CAR-T cells have focused on targeting blood cancers that express CD19, a cell surface receptor that is ubiquitously expressed on a broad range of differentiated B cells, but not on hematopoietic stem cells or other cell types, thus limiting the potential for ‘off-target’ side effects. Since CD19 is expressed on all B cells, patients who receive anti-CD19 therapy will have a complete loss of B cells (both normal and cancerous) and thus be unable to produce immunoglobulins. However, B-cell aplasia resulting from anti-CD19 treatment can be managed with administration of intravenous immunoglobulin to maintain proper IgG levels (35). Some examples of the types of responses being seen using CAR-T therapy in various hematologic cancers include:

ALL: B-cell acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells that results in overproduction of cancerous lymphoblasts in the bone marrow, which inhibits the production of normal red and white blood cells. CD19-targeted CAR-T therapy was shown to be highly effective for the treatment of relapses/refractory pediatric and adult ALL, particularly in relation to previous treatments. A study of 609 adults from the U.S. and U.K. with relapsed ALL conducted before the use of CAR-T found an overall survival (OS) at five years of only 7% (36). In contrast, studies testing CD19-targeting CAR-T have resulted in complete response rates from 70-90% in heavily pretreated patients (37, 38).

CLL: Chronic lymphoid leukemia (CLL) is characterized by uncontrolled growth of B cells in the bone marrow and blood that ultimately results in the exclusion of normal blood cells. Responses to anti-CD19 CAR-T therapy have not been quite as robust in CLL as in ALL; however, an overall response rate of 57% was noted in a small pilot study (n=14) with persistence of complete response in two patients lasting more than four years (39). In a follow-up Phase 2 clinical trial involving two different doses of cells (n=24), the overall response rate was 42% (40).

NHL: Non-Hodgkin’s lymphoma (NHL) is a group of blood cancers that includes all lymphomas except for Hodgkin’s lymphoma. Many research groups have studied anti-CD19 CAR-T therapy for NHL, including a small study of 15 patients that resulted in a complete remission in eight of the patients (41). Of the seven evaluable patients with diffuse large B-cell lymphoma (DLBCL), an aggressive form of lymphoma, four had complete remissions.

- Additional CAR-T Targets

CD19 is an excellent target for CAR-T therapy based on the fact that it is ubiquitously expressed by patients suffering from a diverse range of B-cell malignancies. Additional targets for hematological malignancies have been identified, including CD22, ROR1, CD30, B-cell maturation antigen (BCMA), CD138, CD33, and CD123.

For solid tumors, there are fewer potential antigens from which to target based on the heterogeneity of antigen expression in solid tumors. Also, the tumor microenvironment in solid tumors is more immunosuppressive than for hematological malignancies and ‘on-target, off-tumor’ toxicity is more problematic as most target antigens for solid tumors are expressed in other organs. Targets currently being tested for solid tumor treatment with CAR-T include mesothelin, GD2, and EGFRvIII.

Cancer Moonshot & 21st Century Cures Act Provide Funding for Immunotherapy

During the 2016 State of the Union, President Obama appointed Vice President Joe Biden to lead a new, national “Moonshot” initiative to eliminate cancer. The National Cancer Moonshot is intended to accelerate research efforts and break down barriers to progress by enhancing data access while facilitating collaborations between researchers, doctors, philanthropies, and biotechnology and pharmaceutical companies. The goal of the initiative is to bring about a decade’s worth of advances in half that time while increasing the number of therapies available to patients, and improving cancer prevention and early detection.

To help ensure that the goals of the Cancer Moonshot are achieved, a Task Force was assigned to consult with external experts to produce a detailed set of findings and recommendations to make the most of federal investments, private sector efforts, targeted incentives, and other mechanisms to support cancer research. The Task Force released a report in October 2016 that described actions launched under the Cancer Moonshot during the first year, as well as longer-term plans for the future (42).

In addition to the Task Force, a Blue Ribbon Panel of leading experts from a broad range of scientific areas was constructed to come up with a set of recommendations for achieving the Cancer Moonshot’s goal of making 10 years worth of progress against cancer in just five years (43). One of the recommendations was to create a translational science network devoted exclusively to immunotherapy to discover why immunotherapy is effective in some patients but not in others.

Funding for the Cancer Moonshot was provided as part of the 21st Century Cures Act, a bill signed into law by President Obama that boosts funding for medical research, allows for the FDA to approve certain therapies based on new expedited pathways, and provides assistance to combat the country’s growing opioid abuse epidemic. Of the $4.8 billion in new funding for the NIH provided by the 21st Century Cures Act, $1.8 billion is allocated for the Cancer Moonshot. I believe that companies developing cancer immunotherapies will likely be at the receiving end of some of this money in the form of research grants and/or clinical trial assistance.

Companies Developing Cancer Immunotherapies

Biotech and pharmaceutical companies of all sizes are developing cancer immunotherapies; thus, investors with all risk tolerances can likely find investable ideas to fit their comfort level. Below I’ve included a brief overview of various companies that can serve as a starting point for investors for further investigation.

- Large Cap Companies

Bristol-Myers Squibb (BMY): In 2011, the FDA approved the anti-CTLA-4 monoclonal antibody Yervoy® (ipilimumab) for the treatment of metastatic melanoma. It was the first drug shown to extend survival in patients with metastatic melanoma. In the first three quarters of 2016, BMY reported $789 million in revenue for Yervoy®. In 2014, the FDA approved the anti-PD-1 monoclonal antibody Opdivo® (nivolumab) for the treatment of melanoma. Since then, the FDA has approved Opdivo® for second-line non small-cell lung cancer (NSCLC), advanced renal cell carcinoma (RCC), Hodgkin lymphoma, and metastatic head and neck cancer. In the first three quarters of 2016, BMY reported Opdivo® revenues of $2.4 billion.

Merck (MRK): In 2014, the FDA approved the first anti-PD-1 antibody, Keytruda® (pembrolizumab), for the treatment of advanced or unresectable melanoma. Since then, the FDA has approved Keytruda® for second-line NSCLC, first line NSCLC in patients with high PD-1 expression, and metastatic head and neck cancer. In the first three quarters of 2016, Merck reported Keytruda® revenues of $919 million.

Roche (RHHBY): In 2016, the FDA approved the first anti-PD-L1 antibody, Tecentriq® (atezolizumab), for the treatment of bladder cancer and second-line NSCLC. There does not appear to be much of a difference in treatment effects between anti-PD-1 and anti-PD-L1 antibodies; thus, Tecentriq® is likely to take market share from both Opdivo® and Keyruda®.

Amgen (AMGN): In 2014, the FDA approved the bispecific T cell engager (BiTE) Blincyto® (blinatumomab) for the treatment of ALL. BiTE’s consist of two monoclonal antibodies joined together. Blincyto® consists of one end binding to CD3 on T cells and the other end binding to CD19 on B cells. Approval was based on the results of a Phase 2 trial in which 42% of 185 patients achieved complete remission following treatment with Blincyto®. In the first three quarters of 2016, Amgen reported Blincyto® revenues of $86 million. In 2015, the FDA approved the oncolytic virus Imlygic™ (talimogene laherparepvec) for the treatment of advanced melanoma. Imlygic™ is a genetically engineered herpes simplex virus I, which preferentially kills cancer cells, and is estimated to have peak worldwide sales of close to $400 million (source: EvaluatePharma).

Novartis (NVS): While the companies mentioned above have focused on the development of antibodies targeting checkpoint inhibitor proteins, Novartis has focused mostly on CAR-T. The company recently presented data from its lead compound, CTL019, in children and adolescents with relapsed/refractory ALL that showed 82% of those treated achieved a complete remission or complete remission with incomplete blood count recovery at three months post treatment. Novartis is expected to file for approval of CTL019 in ALL in the first half of 2017.

- Mid Cap Companies

Juno Therapeutics (JUNO): Juno is focused on developing CAR-T therapies for the treatment of hematologic and solid tumors. The company’s lead program, JCAR015, is being developed for the treatment of adult ALL and NHL. Recently, the FDA put a clinical hold on the Rocket trial of JCAR015 due to the death of two patients. The FDA had put a clinical hold on the same trial in July following the death of three patients; however, the hold was quickly lifted following a change in the preconditioning regimen that was supposed to alleviate the chance of patient deaths. Thus, the future of that program is unclear. In addition to treatments targeting CD19, the company is also developing CAR-T therapies targeting WT-1 (for NSCLC and AML), L1CAM (for neuroblastoma and solid tumors), and CD22 (for B cell malignancies).

Kite Pharma, Inc. (KITE): Kite is developing CAR-T therapies for the treatment of hematological cancers and T-cell receptor (TCR) therapies for the treatment of solid tumors. The company recently presented data from the pivotal ZUMA-1 trial of KTE-C19 in patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) that showed 47% of patients treated with KTE-C19 achieved complete remission. Importantly, grade ≥3 CRS was only reported in 13% of patients, and there were no deaths reported attributable to treatment with KTE-C19. The company is planning to submit a BLA to the FDA for KTE-C19 in the first half of 2017.

Bluebird Bio Inc. (BLUE): Bluebird is developing gene therapies for rare diseases and CAR-T therapies for hematological cancers. The company’s lead program, bb2121, targets B cell maturation antigen (BCMA) and is currently being evaluated in a Phase 1 study for the treatment of relapsed/refractory multiple myeloma. Bluebird's bb2121 is being developed in collaboration with Celgene (CELG). The company recently announced a 100% overall response rate with doses of bb2121 above 5x107 CAR T cells, and there was no grade ≥3 CRS. The study is ongoing to identify a recommended Phase 2 dose.

Bellicum Pharmaceuticals, Inc. (BLCM): Bellicum is developing CAR-T and cell therapies for the treatment of cancer and rare diseases. The company has developed a set of molecular switches that allows a response to be either shut-off or turned on depending on the situation. The company’s lead CAR-T product is BPX-601, which includes a dual co-stimulatory domain that places the costimulatory signal on a rimiducid-controlled switch. Thus, the cells are only activated upon the presence of antigen (prostate stem cell antigen, or PSCA, in the case of BPX-601) and administration of rimiducid, a small molecule drug that has no other target inside the body. This control allows for full activation of the cells in the presence of antigen and attenuation of the reaction in the event of side effects (e.g., severe CRS). The company has initiated a Phase 1 clinical trial of PBX-601 in patients with non-resectable pancreatic cancer.

- Small Cap Companies

Vaxil Bio Ltd. (VXL.V): Vaxil is developing ImMucin™, which targets MUC-1, a unique cancer antigen with high specificity to malignant cells, and results in a potent stimulation effect on T and B cells. It was recently shown to cooperate with leading checkpoint inhibitors, such as anti-PD1 and anti-CTLA-4 antibodies, in eliciting an anti-tumor proliferative response in bone marrow and blood samples derived from multiple myeloma patients. Additionally, a positive response was observed using a combination with immune-modulating drugs such as lenalidomide. Moreover, the company was also successful in deriving monoclonal antibodies against MUC-1 and recently submitted a patent application for them. ImMucin, and its derived antibodies could ultimately serve as starting materials for the development of specific T cell therapies such as CAR-T and allogeneic T cell transplantation. Since the safety of ImMucin has proven excellent and it has the capacity to work across immunologic barriers (HLA), it appears to be a natural candidate to combine with these modalities and others.

Pieris Pharmaceuticals, Inc. (PIRS): Pieris Pharmaceuticals is developing Anticalins®, which are a novel class of therapeutic proteins that can be engineered to bind any biological target. The value proposition for Anticalins® is that they are easily combined in multimeric formats and can be genetically combined with monoclonal antibodies to make products capable of targeting multiple antigens. The company is developing multiple cancer immunotherapy compounds, with the lead compound (PRS-343) consisting of an Anticalin® targeting 4-1BB attached to an anti-HER2 monoclonal antibody. The company is also developing an anti-PD-1 antibody attached to an Anticalin® targeting an undisclosed target. PRS-343 is expected to enter the clinic in 2017.

Enumeral Biomedical Holdings Inc. (ENUM): Enumeral is developing monoclonal antibodies against multiple immune checkpoint proteins. The company has discovered a set of next generation anti-PD-1 antibodies that elicit effects differently from the currently approved anti-PD-1 antibodies Opdivo® and Keytruda®. In addition, the company is building a pipeline of antibodies that target additional checkpoint proteins including TIM-3, LAG-3, TIGIT, and VISTA.

Trillium Therapeutics, Inc. (TRIL): Trillium’s lead program, SIRPαFc (TTI-621), targets the CD47 “do not eat me” signal. SIRPα is expressed on macrophages and when bound by CD47, a molecule expressed in high levels by a number of different tumor types, the macrophages are inhibited from phagocytosing the malignant cells. SIRPαFc binds to CD47 on tumor cells and prevents the “do not eat me” signal from reaching macrophages. The company recently presented initial data from a Phase 1 study of TTI-621 in patients with advanced hematologic malignancies and noted several patients experienced prolonged progression-free intervals, and one patient had a partial response. Due to its unique mechanism of action, pairing TTI-621 with an anti-PD-1 treatment could provide an enhanced anti-cancer effect.

BriaCell Therapeutics Corp. (BCT.V): Briacell is developing BriaVax™, a whole-cell vaccine, as a targeted immunotherapy for breast cancer. It is assumed to work by inducing an immune response against antigens expressed by both BriaVax™ and breast cancer cells from the patient. Since the immune response following BriaVax™ treatment may be dampened by immune checkpoints expressed by the tumor, a combination therapy consisting of BriaVax™ and one or more checkpoint inhibitor targeting antibodies, such as Opdivo® or other PD-(L)1 inhibitors, may result in an enhanced anti-cancer response. Also, BriaVax™, due to a vastly different mechanism of action, may also exhibit additive or synergistic effects with more traditional treatment approaches such as chemotherapy or radiation and should work well with targeted therapies such as PARP or aromatase inhibitors.

Final Thoughts

It’s an exciting time for researchers, doctors, and patients, as more effective and less toxic cancer treatments are being developed at a remarkable pace. The cancer immunotherapy market is estimated to reach over $100 billion by 2021 (source: Marketsandmarkets), thus there are plenty of opportunities available for investors to take part in the revolution in cancer treatment. The list of companies shown above is certainly not all-inclusive but designed to give investors a head start on identifying names that are developing the next breakthroughs in cancer therapy. Feel free to leave additional ideas in the immunotherapy space in the comments below.


Please see important information about BioNap, Inc. and our relationship with company's mentioned in this article in our Disclaimer.
BioNap owns stock options in BCT.V. We hold no other material position in any company discussed above, but reserve the right to establish a position in any name in the future.


  1. How would you weight the small caps if you had to buy them all in your portfolio... thnx

    1. I don't really like to do stuff like that because it comes too close to providing specific investment advice. Everyone needs to make their own decision. I like BCT.v and PIRS. I've owned PIRS off and on in 2016. Thinking about getting back "on" it. I also like ENUM, although it might be a bit early-stage. VXL.v is very interesting and I'd like to see their program get moving.

    2. Understood, thank you


      This PIRS article believes its severely undervalued, never heard of the research firm

  2. What do you think of ATNM going into 2017?

    1. Big fan! It's not really an "immunotherapy" company so it didn't fit in with this model, but I do like the story. I think it could go similar to CPXX in the coming year or two.

  3. Why didn't you mention IMNP?

    1. Ceplene is certainly an interesting I/O drug and it likely would benefit from combination with checkpoint inhibitors. I plan on discussing it further for investors in the coming weeks.

  4. What are your thoughts on MabVax for early 2017 ? Is this a company to watch for Cancer Therapy Breakthroughs ?

    1. Yep, I actually own some shares (unfortunately at higher prices). It's not really an immunotherapy, so I did not include them in this article.

  5. Understand you couldn't mention every I/O company, but why no mention of ZIOP, as it has one of cancer's luminaries as CEO (Lawrence Cooper), a close relationship with MD Anderson, and two potentially interesting technologies: RheoSwitch and Sleeping Beauty. Any opinions on how meaningful those technologies are likely to be and whether ZIOP warrants consideration?

    And, how about ADXS, with its (almost) unique Lm technology?

    1. I like ADXS, although ADRO recently ran into some trouble with their LM technology, so I'm not sure if that is good news or bad news for ADXS! That was an entirely new area of I/O I didn't get into, so I didn't mention the LM or vaccine companies, except BCT.V.

      As for ZIOP, I stuck with the larger CAR-T players of JUNO, KITE, and NVS, and then decided to mention BLUE given their P1 MM data and then BLCM because they have a pretty unique technology. I like BLCM > ZIOP, but I'm certainly not bearish on ZIOP. Like you said, I could not mention everyone!

      Thanks for reading!

  6. Yes, ADRO did run into problems, but without getting into the technical details, their Lm is different from ADXS's. ADXS originated Lm. The challenge/ benefit is that Lm remains in the body long after administration (years, possibly decades). The good news is it can keep fighting any remaining cancerous cells it is targeted to attack (and versions can be designed to attack a wide range of cancer cells). The bad news is, technically, people have ongoing listeriosis. This should not be a problem because this listeria does not cause disease. Still, ADXS was halted for several months starting in September 2015 because of a death due to this concern: could Lm mutate back into an infectious agent, especially since an internal prosthetic device was colonized with listeria. After months of research, the answer is almost certainly "no." However, trials (I believe) now exclude people with internal prosthetics that could be a reservoir for bacterial growth.

    Correct me if any of the above is mistaken.

    I think ADXS (or ADRO -- although I think they have an inferior Lm strain) could be an excellent complementary investment to the CAR and TCR-oriented therapies in development. I think CARs are unlikely to have much ultimate impact: too expensive, too problematic. TCR may work, but a long way to go to prove that out. Lm may come sooner and prove equal/ better in effectiveness and safety profile, especially with neoantigen targeting (which ADXS has partnered with Amgen to develop).

  7. Briacell also trades on U.S. under BCTXF, the XF stands for XTRA FINE.

    1. Hmm... I'm not sure that's correct.