Medicare Spending

A recent study tries to correct the misconception of Medicare spending. MIT reports:

After examining millions of medical records, the study found that although Medicare spending is concentrated among people who die, there is very little Medicare spending on patients whose death within the year is highly likely. For example, the researchers discovered, less than 5 percent of Medicare spending is applied to the single highest-risk percentile of all individuals — and their predicted one-year mortality rate is still just 46 percent. “What we discovered is, very little money is spent on people who we know with high probability are going to die in a short amount of time,” says ..., a professor in MIT’s Department of Economics and co-author of a paper in the journal Science that details the study’s findings. To the extent that such cases exist, she adds, “they’re just not the drivers of spending” in bulk. The study also illuminates the general circumstances of late-in-life mortality. Fewer than 10 percent of people who die in a given year have a predicted one-year mortality rate over 50 percent. As the researchers found, even when people are admitted to a hospital in what turns out to be their last year of life, fewer than 4 percent of those patients have a predicted one-year mortality rate of 80 percent or higher at the time of admission.

So I guess "words mean something".  For decades politicians and policy wonks have spouted the inefficiency of Medicare. In reality if 5% is spent on the last year of life, and if Medicare starts at 65 and life expectancy for a person at 65 is to 82, then the 18 years indicates that 5% is less than the annual allocation. In effect, known last year expenditures are below average.

Between using the right words and the right numbers one comes up with a grossly different answer. The result, one must question everything, especially if from a Government source.

Summer Truly Begins

The daylily species, Hemerocallis citrina, is a fragrant night blooming flower found often in China.

One knows summer is here when it begins to bloom. I did last night.

If one has a house surrounded by these then at night the fragrance is wonderful!

Way Back

The above is Midland Beach on Staten Island. Some 60 years ago I started my career there as a Lifeguard and I recall the beach packed with people every day! Now it is empty. Guess they went to the Jersey Shore!

Also look at the "sand", it is clay brown and relatively unappealing. As with anything under the control of New York City these days the bath houses are collapsing but fortunately closed.

Yield Curve

The yield curve is flattening rapidly. Now look at the spreads:

The above is longest to shortest.

The above is a more reasonable set of points but again notice the collapsing.

What does this mean?

1. Our debt is short term, namely we now must pay more in interest.

2. Long term reflects growth, which is stagnating. Yet GDP seems to reject that. Perhaps the bloat on the FED BS.

3. This is also a warning for a recession. Hold on to your hats!

Harvard, Admissions and Athletes

The NY Times reports:

In its admissions process, Harvard scores applicants in five categories — “academic,” “extracurricular,” “athletic,” “personal” and “overall.” They are ranked from 1 to 6, with 1 being the best.

 Interesting. Let's examine these:

1. Academic: This is a weighted number of GPA if such exists, class ranking, again is it exists, and SAT or equivalent scores. The weighting is often based on what type of secondary school one went to. Thus if it were Exeter I suspect one would have a strong position whereas if it we Robert Wagner HS on Staten Island you may be somewhere down the pile.

2. Extracurricular: Curing AIDS in Uganda perhaps could get you a few points as would be having been elected as a State Senator, Democrat of course.  In the old days a VP on the Student Council would work but today when everyone gets a prize one wonders how this works.

3. Athletics: Now here is a real quiz. People fall into three categories. No sports at all, perhaps most Nobel Prize winners fall in this collection, team sports, the prep school winners are here as are large public schools, and the individual sports. The latter is where we get entrepreneurs. I did boxing and was a lifeguard, both required individual singular performance, and in boxing it was real time. So how does Harvard weight these?

4. Personal: Oh yeah, try to do this one folks. MIT used to have alumni do interviews but they disbanded this. I did it for 25 years and saw a large swath of students, and a few, who were accepted despite my concerns, all left before graduation. That personal contact is important but, well it is personal.

5. Overall: Just what this means I cannot tell despite a few readings. The selection used to be based on Faculty reviews, now there is a politically correct admissions committee. Thus the applicant must play to their biases rather than the facts.

It will be interesting to see how this litigation ends.

What If?

Ars Technica has an article on the proposed tunnels connecting O'Hare to downtown Chicago. They note:

The Boring Company has released details about its proposed system already—it calls the system a "Loop," as in a modified version of the "Hyperloop" idea. (This means there will be a Loop to The Loop—very cute, Chicago.) Unlike the Hyperloop idea, the tunnels will not be depressurized. The company has stated that its electric pods would travel at 125-150 miles per hour. The city of Chicago's press release confirmed that The Boring Company has proposed vehicles that will travel faster than 100 miles per hour.

 Nice idea bu:

1. What if there is a breakdown
2. What if there is a burst water pipe flooding the tunnel
3. What if there is a health emergency
4. What if there is an earthquake
5. What if there is a broken gas line
6. etc

Namely these claustrophobic tubes that are reminiscent of birth canals are not like New York subways, with multiple entry and exit locations where emergency facilities can be brought to bear. This may be a great idea if it works all the time, but we know that such is not the case. There does not seem to be any discussion of these issues.

There seem to be only two points of entry, the beginning and the end. That is a long way to go without any problems. Just look at the DC Metro.

The Battle of the Distribution Channels

It appears that Comcast is trying to get the Fox content for its distribution channel. As the NY Times reports:

Comcast announced an offer worth $65 billion for the bulk of 21st Century Fox’s businesses on Wednesday, setting up a showdown with the Walt Disney Company for Rupert Murdoch’s media empire. The all-cash bid by Comcast, the largest cable company in the United States, came a day after a federal judge approved a merger between AT&T and Time Warner. Comcast executives had awaited the decision in that case before mounting their bid for 21st Century Fox.

What does this prove? Content without a customer is worthless. A customer with no content is equally worthless. Distribution gives customers access. But customers are fickle and want all sorts of stuff. Also customers are getting rather sick of paying for stuff they do now want or outright despise, like ESPN for some customers. Thus this is a tricky move.

The customer does not want bundles any longer, the know the CATV scams all too well. Average CATV rates have doubled in eight years. Nothing changed, just the price. The cable converter is priced at about $15 per month per converter and it is a relic. There is no option even though the FCC allows it. Then again we ask; what FCC, at least under current management.

The game here between Comcast and AT&T is interesting. AT&T has the better connection via 5G, if and only if they understand what they have. Somehow they seem clueless. Cable is a dying technology. Also Cable is hated by its customer base and it seems Comcast is at the top of this list. 

Then again there is Verizon, same 5G asset, but their brain trust bought AoL and Yahoo, two apparent boat anchors. Thus the game is between Comcast and old technology and AT&T and a winning technology is they can understand what they have. 

This will be an interesting play.

Attitude?

The Telegraph has a telling piece, especially explaining why we Irish have this, well let's call it our attitude, towards the English. The author is one Annabel Fenwick Elliott, a Dickensian name if ever there was one, who says it is her "right" to assault the customer sitting behind her by leaning her seat back no matter what. Yes assault, look up the term fair madam, it is in English Common Law. So are the remedies.

Now what specifically sets one off? The following:

Not only do I keep my seat reclined on every flight, in every situation, with the sole exception of meal times, but I slyly push that button - ever so gently - as soon as the plane takes off so that it tilts back with the force of the ascent, rather than wait until we’ve reached altitude, in a motion which feels less abrupt. Again, until now, this to me was just common sense and in fairness, not once have I ever been called out on it....“But I’m tall!” I hear you cry. “My knees are already crushed!” Being tall is an advantage in some situations (reaching things, attracting a mate) and a disadvantage in others (public transport, shopping for jeans). The average height of a man in the UK in 5ft 9in, a woman is 5ft 3in. If you happen to be taller, this is not your fault, but equally it is not my problem, not on a plane where all the seats are the same size.

 Well it is your fault now. You have just expressed intent, and element of English Law, mens rea if you will for those still properly educated. And one wonders why there is a general distaste for the English. Other than their occupying lands not their own for centuries, and in turn oppressing the local folks, the law they developed does have a double edge.

Oh, by the way, I am 6' 3" and have long legs which lock immediately upon sitting. And also Ms Fenwick-Elliot-Dunstable-Wentworth-Buckingham-whatever, my solicitors are not that friendly. See ya!

You Want a Phone; Black and Rotary Dial

The AT&T Time Warner merger presents a set of interesting questions, many of which the Court in its wisdom or lack thereof failed to address. Two things happened this week, and they are closely related. First this merger which I shall comment on and second the FCC destruction of common carriage. They are tightly related.

To use a well used phrase, we are in an information society. There are providers of this "information" and there are channels for its distribution. Typically in the US we have at times tried to keep them separate. The Judge Greene MFJ actually mandated that, for the Judge there saw the power of owning both.

For if you owned the distribution channel and you owned one of the arguably many sources of "information" then you could leverage out your competitors and control what the consumer sees. The FCC rule now mandates that.

McLuhan said the Medium was the Message but he meant that if one controlled the medium, namely the channel and content, you controlled what people saw as "truth". You had the ultimate tool for propaganda.

Do the antitrust laws allow for this type of control? I would argue not but the Judge in this case seems not to agree.

Thus the most serious threat to an open democratic society is the ownership of content and distribution. The old decision to break apart movie theaters and movie makers in the 1940s saw that. Apparently the current Judge disagrees.

A key point is also the development of 5G. My fear is that AT&T is reverting to its old ways, really old ways. A brief tale from the past may be worth telling. Fred Kappel was CEO of AT&T in the 60s. Fred was there when Bell Labs/Western Electric developed the Electronic Switching System No 1, No 1 ESS. Now this was kind of electronic but still had many mechanical parts. A large piece of the costs of telephones was maintenance and the old mechanical switches required lots of this, Fred wanted a fully electronic system. Here the battle began. The powers to be were adamant on slow change because the Bell System made its money, profit, based upon a return on investment, and the more costly the plant the more profit. You see profit in the phone company was not revenue less expenses, its was a percent return on capital plant, and the more inefficient you were the more you made.

So how does this relate to AT&T today? Simple, now that they own content they must get a return. How to do that? Simple, slow roll 5G, allow no new content entrants via wireless, and go back to a black rotary dial phone! Thanks Judge.

You see, the objective of the Antitrust laws is to protect competition, namely the consumer's ability to choose, NOT protect the competitors. Protecting competition means simply allowing for a multiplicity of competitors, not vertical and horizontal merging.  Any third year law student looking at Antitrust Law should understand that. How was this point missed in this case?

Finally, one could consider the following analogy:

1. ATT owns the dominant trucking company in the US with an exclusive government franchise (the wireless licenses ATT got "free" decades ago, yes free, and they block any competition)

2. The US govt has given ATT trucking the right to not have to carry anyone else's produce (the FCC elimination of net neutrality)

3. ATT buy McDonald's, local stores and their "production" facilities (read Time-Warner)

4. You go out to buy food and all you can now get is McDonald's (read ATT) since no other vendor can get their goods shipped in.

That is the analogy. They own the distribution channel which is a substantial barrier to entry and now can "supply" whatever they want.

Wow, I see Someone Listened!

Yep, we went from 200Kbps to 116,000Kbps, almost a 1,000 fold increase, and the IP addressed changed as well! It will be interesting to see what AT&T does with their new found love!

One should remember, the asset is the wireless license. There are just a few and 5G will blow fiber out of the water, despite what lawyers think. Content is real tricky. Look at the mess Verizon has with its media stuff, AoL and Yahoo.

The revenue will become more selective buys and less eyeballs. With a 5G data driven approach one can subscribe to what they want. Unless of course your carrier owns the content they want you to see! So did the Court err? Think about it.

Debt Payments

The following chart should be terrifying. It is the quarterly debt payments.

We are on our way to $600B per quarter of $2.4 trillion a year. It was less than half of this in 2008. Well no surprise since debt has more than doubled but it is worse since much of the low cost short term debt is coming due and must be rolled over at fantastic increases!

Words Mean Something, I Think

 The NY Times notes the following:

A Harvard-trained economist with outside-the-mainstream views. Mr. Navarro is a former a professor at the University of California, Irvine, who holds a doctorate from Harvard. He is one of the only credentialed economists in Mr. Trump’s inner circle.

Now I do not know this fellow and I know even less about trade. In fact I am not a fan of economists period so having just one may even be a good idea. But that is not the point either.

The NY Times had a style book and editors. So here is where I am going off the track. One trains a dog, a horse, maybe even a mouse. One never trains a cat, but I leave that to cat lovers. Harvard "educates" people, MIT even does that. The Commonwealth of Massachusetts used to have Training Schools for Juvenile Delinquents. But Universities, especially Harvard, do not "train" people.

Thus I ask the noble NY Times, why did you select this verb? It most likely is not allowed in your style book, and its usage, besides being derogatory, states that the article is political and not factual. One perhaps must reject all of its contents.

Now on to tariffs. Everyone one seems to be for free trade, even the President suggested the elimination of tariffs. But it may be perhaps of value if someone could lay out the current tariffs. Let's just start with Canada. Having a home on northern New Hampshire I always see a constant flow of trucks from Quebec coming south, even with wood. That is somewhat like bringing coals to Newcastle but then again I never spent any time in the lumber trade.

So my point is simple. Stay with the facts. Harvard has not trained anyone since pre-WW II NROTC units and tariffs really need to be let out in the sunshine. Oh yes, and for the economists, perhaps zero is a good number.

Adoptive Cell Transfer

As understanding of the immune system has progressed its use as a therapeutic for various cancers has also moved forward. This hand in glove approach has allowed one to go from observation to utilization to modification and then cycle again. The area of tumor infiltrating lymphocytes and their application in the area of adoptive cell transfer has been a topic of interest for almost three decades. The presence of T cells around tumors is a common occurrence. For example in malignant melanoma there is often such a proliferation seen upon biopsy. 

The question then is; if the immune system acts accordingly then why does it not follow through and destroy the tumor? We now understand some of the basics of this process and one suspects a great deal more will be learned. However the proliferation of the T cells, called Tumor Infiltrating Lymphocytes, TILs, led early investigators to try and utilize them as a therapeutic. This was done by ex vivo acceleration and proliferation of the cells and implanting them back in the patient. This is adoptive cell transfer. This we shall focus on in this brief note.

Rosenberg and his Lab have for nearly 40 years been investigating this area. In a 1985 NEJM paper he wrote about his work with autologous lymphokine-activated killer (LAK) cells:

The administration of LAK cells in conjunction with interleukin-2 as reported in this paper represents a possible new approach to the treatment of cancer, with potential applicability to a wide variety of tumors. A major advantage of this approach is its broad antitumor specificity. It should be emphasized, however, that this study involved a limited number of patients and that the frequency and duration of the clinical responses have yet to be determined.

The practicality and safety of administering this therapy to large numbers of patients also remain to be fully defined. The similarity of our initial experience in patients to our prior experience in mice, however, offers hope that this therapy can be made effective against human cancer.

What Is ACT

As noted, this examination of TILs and their function has been examine for decades. For example, in 1991 Jicha et al (in Rosenberg's Lab) had noted:

Interleukin 7 (IL:7) is a 25-kD cytokine that was initially described as a pre-B cell growth factor. This cytokine has also been shown to have T cell proliferative and differentiation effects. In this report, we demonstrate that antitumor cytotoxic T lymphocytes (CTL) generated by secondary in vitro sensitization of draining lymph node cells in IL7 are effective in treating 3-day syngeneic methylcholanthrene (MCA) sarcoma pulmonary metastases in mice.

In vivo titrations comparing IL7 to Ib2 antitumor CTL show that they have equivalent potency in adoptive immunotherapy. IL+-7 antitumor CTL generated against MCA sarcomas of weak immunogeneity are also tumor specific in their in vivo efficacy. This study represents the first successful use of a cytokine other than IL-2 for the generation of cells with in vivo efficacy in cellular adoptive transfer.

Earlier Belldegrun et al (also from Rosenberg's Lab) noted:

The identification, isolation, and adoptive transfer of selected subsets of immune cells with specific antitumor reactivity into tumor bearing patients to mediate cancer regression in vivo is a prime goal of tumor immunology. Currently, however, there are no available techniques for generating such lymphoid cells with reactivity against specific tumor antigens in the human.

Recent experiments have demonstrated that the adoptive transfer of lymphokine-activated killer cells plus IL-2 can mediate tumor regression in a variety of animal models and human tumors as well. This approach, however, requires the transfer of large numbers of sensitized fresh lymphocytes, i.e., more than 10¹¹ immune cells, into tumor bearing humans, along with the systemic administration of relatively high doses of RIL-2 (100,000 units/kg body weight i.e. every 8 h).

Many human tumors are infiltrated with chronic inflammatory cells, including lymphocytes. We have recently identified a population of lymphoid cells infiltrating murine tumors that could be expanded in vitro in IL-2 and, when adoptively transferred, were capable of totally eliminating 3-day established pulmonary metastases. When compared to LAK cells, these TIL cells were at least 50 times more potent in mediating the therapy of established micrometastases. The simultaneous administration of IL-2 enhanced the in vivo therapeutic effective ness of the adoptive transfer of TIL, although high doses of TIL alone were also effective. The greater therapeutic efficacy of TIL compared to LAK cells in the treatment of established metastases in mice raises the possibility that TIL isolated from human tumors and expanded in vitro in IL-2 may similarly be effective for the treatment of human cancer.

Now in our current understanding these have again attracted attention as Horton and Gajewski (2018) note:

Tumours from multiple cancer types can be infiltrated by CD8+ T cells (TILs). TILs are thought to be suppressed by multiple immune inhibitory molecules in the tumour microenvironment, and this suppression has been associated with tumour progression.

Therefore, despite tumour infiltration, almost all tumours containing TILs will progress if not treated. While several immune inhibitory mechanisms have been identified, immune inhibitory receptors expressed on activated T cells, like CTLA-4 and PD-1, have received the most attention over recent years owing to the immense clinical success of PD-1 and CTLA-4 neutralizing antibodies. The engagement of inhibitory receptors expressed by TILs is thought to render TILs dysfunctional.

However, evidence from both human tumour samples and mouse models has suggested that, despite inhibitory receptor expression, TILs are not functionally inert and actually retain the ability to proliferate, produce IFN-g and show ex vivo cytotoxicity.

These observations raise the question of why activated TILs are not able to spontaneously control progressing tumours, and how tumours that contain TILs might sometimes be resistant to immunotherapies such as checkpoint blockade. Current immunotherapies can induce durable tumour regression; however, they benefit a minority of patients: finding new strategies to increase the response rate to immunotherapies is of great interest to both researchers and clinicians.

There are many dimensions available for employing the immune system. Many current foci relate to the T cell elements of the adaptive system. There are also a multiplicity relating to the innate system including the NK or natural killer cells. The overall approach requires an understanding of two things: (i) what makes a tumor cell different and how does it tend to protect itself, (ii) how do immune systems identify and attack aberrant cells. On the one hand we look at the malignant cell and how it expresses itself, which we know is arguably an ever changing process. The second element is how can we use and manipulate the bodies basic immune system, and here it should be both adaptive and innate.

Multiplicity of Ways

There are a multiplicity of ways in which the immune system may attack cancer cells. We summarize this in the figure below. We have discussed checkpoint issues and CAR T cells previously and herein we focus on TIL and ACT mechanisms. All of these mechanisms shown below are somewhat variants of each other as we shall discuss. TIL/ACT mechanisms are the oldest in concept and are in many ways a brute force method of attacking the cancer cells in larger volume than they would have been in vivo.

 We will then focus on the interrelationship between the cancer cell and the immune cell. For each we ask how they are identified, how they act, and how they may protect themselves. We summarize that below. The battle is between an immune cell and a cancer cell. The cancer cell can be identified but it can also protect itself. The self-protection is inherently part of its ancestry as a descendent of the individuals own cell line. It is a protection against auto-immune diseases. In contrast the immune cell can detect cells that do not belong, and as such can then emit attack mechanisms that destroy the unwanted invader. Immunotherapy is thus a balance between survival and destruction.

 Comparisons

We briefly look at a comparison of some of the techniques. From Yee we have the following diagram (as modified):

Yee then notes on the above:

Adoptive Cell Therapy is represented by three general approaches:

1) Enrichment and expansion of tumor-infiltrating lymphocytes (TIL) from a disaggregated tumor biopsy sample

2) Genetic transfer of T Cell Receptor (TCR) recognizing tumor antigen-derived peptide-MHC target or Chimeric Antibody Receptor (CAR) recognizing surface tumor protein

3) Enrichment of endogenous antigen-specific T cells from peripheral blood mononuclear cells by in vitro stimulation followed by cell selection or cloning. PBMCs are a source of both antigen-presenting cells and T cells.

Following enrichment, the population of tumor-reactive T cells undergoes rapid expansion of 1000-5000 fold achieving 10 - 100 billion cells for adoptive transfer. Patients often receive a lymphodepleting conditioning regimen pre-infusion followed by exogenous IL-2. In the case of adoptive TIL therapy, patients receive high-dose near ablative or fully ablative conditioning pre-infusion and a course of high-dose IL-2 post-infusion. … ‘young’ TIL are generated using a shortened pre-expansion culture phase prior to rapid cell expansion, enabling production of an infusible T cell product within 5-7 weeks from time of tumor collection.

Here Yee included a multiplicity of techniques. Namely Yee sweeps any method extracting, modifying, and re-implanting T cells as ACT. We examine these somewhat and leave them as all separate.

One must recall that T cells are not alone in this fight against cancer cells. The innate immune system has a powerful set of tools which are used as an immediate attack mechanism and if properly triggered may be of adjuvant usage. We have examined the innate system and its various methods elsewhere. Two strong elements there include the natural killer cells, NK, and the complement chain. Complement has yet to receive a great deal of attention as regards to cancer immunotherapy. Looking at Macor and Tedesco we note:

The contribution of the complement system to the control of tumour growth has been neglected for a long time as the major emphasis has been put mainly on cell-mediated immune response against cancer. With the introduction of monoclonal antibodies in cancer immunotherapy complement has come into play with a great potential as effector system. Complement has a number of advantages over other effector systems in that it is made of molecules that can easily penetrate the tumour tissue and a large majority, if not all, of the components of this system can be supplied locally by many cells at tissue site.

Further advances are being made to increase the anti-tumour efficiency of the complements system using C-fixing antibodies that are modified in the Fc portion to be more active in complement activation. Another strategy currently investigated is essentially based on the use of a combination of two antibodies directed against different molecules or different epitopes of the same molecule expressed on the cell surface in order to increase the number of the binding sites for the antibodies on the tumor cells and the chance for them to activate complement more efficiently.

One of the problems to solve in exploiting complement as an effector system in cancer immunotherapy is to neutralize the inhibitory effect of complement regulatory proteins which are often over-expressed on tumour cells and represent a mechanism of evasion of these cells from complement attack. This situation can be overcome using neutralizing antibodies to target onto tumour cells together with the specific antibodies directed against tumor specific antigens. This is an area of active investigation and the initial data that start to be available from animal models seem to be promising.

Thus we believe that a great deal can be garnered by not only focusing on the adaptive elements but also the innate.

Observations

ACT can be interpreted in a broad manner. We now examine several areas of collateral interest. They are summarized in the following graphic where we have presented 4 of the eight described above.

 Checkpoint Interactions

Cancer cells are derivative of the body's own cells and as such reflect an ability to stop the immune system from destroying them. These surface markers called checkpoints can tell an attacking immune cell not to do so because this cell is part of the whole, even is expressing clear signs of aberrancy. The creation of monoclonal antibodies, Mabs, have yielded tools that work on may cancers and allow for the attack which otherwise would have been halted.

As Liu et al have noted:

Targeted therapies for cancer with small molecules and monoclonal antibodies (MoAb) have led to significant improvement in the long-term survival of multiple malignancies. The discovery of programmed death- 1 (PD-1) and the ligand 1 (PD-L1) has opened the door to the modern era of cancer immunotherapy. It is well known now that many tumor cells are able to upregulate the expression of PD-L1 which leads to anergy of cytotoxic T cells upon PD-1 binding to the ligand. Blocking the PD-1 pathway using monoclonal antibodies against PD-1 or PDL1 can therefore revamp the immune response against tumor cells.

The development of MoAbs against PD-1 and PD-L1 has led to the fast and fundamental paradigm shift in cancer therapy. The anti-PD drugs are the new form of tumor-site immune modulation therapy through resetting immune reservoir in the tumor microenvironment. This is fundamentally different from the conventional chemotherapy and radiation that mainly target cancer cells themselves.

PD-L1 expression on the tumor cells and immune cells have become biomarkers that can assist clinical decisions in the choice of treatment strategies. Biomarker assays for PD-L1 are playing bigger roles and are being routinely done nowadays. However, PD-L1 assays can be highly variable, which makes it a clinical challenge to employ the results. In this review, we summarized latest clinical development of PD antibodies and immunohistochemistry (IHC) assays for PD-L1 biomarker expression in clinical practice.

CIK Cells

CIK or cytokine induced killer cells, have seen use in multiple areas. I have reported on their use in the case of MDS, myelodysplastic syndrome, patients resulting is what the attending physicians have labelled as a cure. As Jiang et al have noted:

The number of immune cells, especially dendritic cells and cytotoxic tumor infiltrating lymphocytes (TIL), particularly Th1 cells, CD8 T cells, and NK cells is associated with increased survival of cancer patients. Such antitumor cellular immune responses can be greatly enhanced by adoptive transfer of activated type 1 lymphocytes. Recently, adoptive cell therapy based on infusion of ex vivo expanded TILs has achieved substantial clinical success.

Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD8 T cells with diverse TCR specificities, possessing non-MHC-restricted cytolytic activities against tumor cells.

Preclinical studies of CIK cells in murine tumor models demonstrate significant antitumor effects against a number of hematopoietic and solid tumors. Clinical studies have confirmed benefit and safety of CIK cell-based therapy for patients with comparable malignancies. Enhancing the potency and specificity of CIK therapy via immunological and genetic engineering approaches and identifying robust biomarkers of response will significantly improve this therapy. The presence of cytotoxic tumor infiltrating lymphocytes (TIL) within tumor is associated with increased survival of cancer patients. Both antitumor adaptive and innate cellular immunity are important for resistance of tumor growth and eventual elimination of cancer.

Theoretically, antitumor cellular immune responses can be greatly enhanced by adoptive transfer of lymphocytes, a term encompassing a strategy in which autologous T or NK cells are acquired from a cancer patient and then activated and expanded ex vivo prior to reinfusion.

Adoptive cell therapy of cancer, first demonstrated in mice more than 50 year ago, has gained momentum in recent years due to impressive clinical experiences with melanoma patients.

This approach is based on ex vivo expansion of large numbers of TILs and selection of tumor-specific T cell lines. The major effectors of TIL cells are phenotypically CD3+CD8+ T cells and their anti-tumor functions are MHC restricted [5]. In contrast to tumor antigen-specific immunotherapy, there is potential utility of non-antigen specific cell-based therapy. Many patients with cancer are ineligible for TIL-based therapy because their TILs do not expand sufficiently or because their tumors have lost expression of antigens or MHC molecules or have extremely low numbers of TILs.

Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD8 T cells with diverse TCR specificities, possessing non-MHC-restricted cytolytic activities against tumor cells. Therefore, CIK cells can lyse tumor cells in a non- MHC-restricted manner and can serve as an alternative cellular immunotherapy.

The CIK approach is to some degree more akin to ACT but that it tries to use a multiplicity of immune cells. We believe that using CIKs with perhaps better targeting and checkpoint inhibitors may have significant advantages in many malignancies.

ACT vs CAR T

ACT can be viewed in broad terms. I believe it is fair to say that the Rosenberg approach is the classic one of removing TILs and then multiply them and strengthen them ex vivo and then place them back in the patient, without any added modifications. CAR-T cell therapy looks at the cancer cell itself and seeks a unique surface marker, such as CD19, and then designs and builds a T cell to attack just that marker. As Ott et al note:

Adoptive T cell therapy, CAR-T cell therapy Adoptively transferred T cells generated from tumor TILs, T cells bearing engineered, tumor specific T cell receptors, and chimeric antigen receptor (CAR) T cells all have shown remarkable anti-tumor activity in select solid and hematological malignancies. CAR T cells and T cells with engineered tumor specific TCRs may have the ability to induce an inflamed tumor microenvironment and therefore to be promising partnering strategies with PD-1/PD-L1 blockade.

CAR-T are effective and clearly more than a passing fad. Yet they are costly to prepare and may miss the critical cancer cells. ACT is a broad brush approach and hopes that the mix of cells may effectively hit the target. However the problem is always the stem cell or cell of origin problem. This is a substantial issue to be faced.

NK Cells: An Option

Natural Killer cells are considered part of the innate immune system. This classification seems to be based upon their sense of immediacy in responding and the simplicity of their response mechanism. However NK cells are very powerful tools in attacking malignancies as well.

As Pahl and Cerwenka have recently noted:

Natural Killer (NK) cells are classically considered innate immune effector cells involved in the first line of defense against infected and malignant cells. More recently, NK cells have emerged to acquire properties of adaptive immunity in response to certain viral infections such as expansion of specific NK cell subsets and long-lasting virus-specific responses to secondary challenges.

NK cells distinguish healthy cells from abnormal cells by measuring the net input of activating and inhibitory signals perceived from target cells through NK cell surface receptors. Acquisition of activating ligands in combination with reduced expression of MHC class I molecules on virus-infected and cancer cells activates NK cell cytotoxicity and release of immunostimulatory cytokines like IFN-.

In the cancer microenvironment however, NK cells become functionally impaired by inhibitory factors produced by immunosuppressive immune cells and cancer cells. Here we review recent progress on the role of NK cells in cancer immunity. We describe regulatory factors of the tumor microenvironment on NK cell function which determine cancer cell destruction or escape from immune recognition. Finally, recent strategies that focus on exploiting NK cell anti-cancer responses for immunotherapeutic approaches are outlined.

One of the concerns regarding immunotherapy is that the panoply of options may at times be shadowed by a single strand of success and thus leaving behind a set of tools of great power. The authors continue in their discussion focusing on the use of NK cells as the entity in adoptive transfer:

Adoptive transfer of NK cells: To potentiate NK cell activity, the application of IL-2 in patients has remained challenging because high doses of IL-2 can result in serious adverse effects and expand regulatory T cells.

As an alternative, NK cells can be (re-)activated ex vivo and used for adoptive cell transfer therapy.

In the case of T cells, adoptive transfer using autologous tumor-reactive T cells (e.g. anti-MART-1) and chimeric antigen receptor (CAR) T cells (e.g. anti-CD19-CD3+-CD28) achieved significant clinical responses in some patients with advanced melanoma or B cell malignancies. These T cells, however, fail to control epitope-negative variants and have the potential for long-time adverse effects on epitope-positive non-malignant cells.

Similar to CAR T cells, genetically-engineered CAR NK cells are currently explored to more specifically direct NK cell cytotoxicity toward cancer cells. Analogous to therapeutic antibodies, this approach enables the killing of cancer cells which are otherwise poorly susceptible to NK cell recognition in addition to ‘natural’ cytotoxicity against epitope-negative cells.

Adoptive transfer of ex vivo cytokine-activated autologous or haploidentical NK cells resulted in favorable responses in a subset of pediatric and adult patients with hematological malignancies without causing graft-versus-host disease in the recipients.

This discussion expands the set of calls used in an adoptive transfer mode. Perhaps there can be alternative beyond these as well. My thoughts would include the complement system and its ability to isolate and neutralize aberrant intruders.

Multifaceted Approach

As much as I find the term "precision medicine" inaccurate, for we really mean accuracy not precision but I suspect this is a politically chosen term, the above approaches represent a collection of tools we now have at our command in treating cancers. In addition we also have pathway modifies such as kinase inhibitors whose use in such cancers as CML truly opened the door to treatment based upon detailed knowledge. One suspects that ultimately cancer treatment will be an integrated usage of all of these therapeutic techniques and not just one at a time. If we have learned anything from the treatment of Hodgkins Lymphoma it is that single threaded treatments are rarely effective and that an integrated approach is essential.

Comparisons

We can now make some overall comparisons as shown below:

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