1. CAR T-cell therapy: the next step towards a holistic treatment of cancer
Scanning electron micrograph of a healthy human T-cell; a 3D render of T-cells attacking cancer cells.
As cancer is a disease which constantly evolves to evade treatment, we need to keep developing more sophisticated therapies with as few-side effects as possible. A new development on this front, holding the attention of many researchers worldwide, is the CAR T-cell therapy
The story so far:
The three major forms of treatment for any cancer are surgery (removing the cancer), radiotherapy (delivering ionising radiation to the tumour), and systemic therapy (administering medicines that act on the tumour). Surgery and radiotherapy have been refined significantly over time whereas advances in systemic therapy have been unparalleled. A new development on this front, currently holding the attention of many researchers worldwide, is the CAR T-cell therapy.
How has systemic therapy evolved?
Systemic therapy’s earliest form was chemotherapy; when administered, it preferentially acts on cancer cells because of the latter’s rapid, unregulated growth and poor healing mechanisms. Chemotherapeutic drugs have modest response rates and significant side-effects as they affect numerous cell types in the body. The next stage in its evolution was targeted agents, also known as immunotherapy. Here the drugs bind to specific targets on the cancer or on the immune cells that help the tumour grow or spread. This method often has fewer side-effects as the impact on non-tumour cells is limited. However, it is effective only against tumours that express these targets.
What are CAR T-cells?
Chimeric antigen receptor (CAR) T-cell therapies represent a quantum leap in the sophistication of cancer treatment. Unlike chemotherapy or immunotherapy, which require mass-produced injectable or oral medication, CAR T-cell therapies use a patient’s own cells. They are modified in the laboratory to activate T-cells, a component of immune cells, to attack tumours.
These modified cells are then infused back into the patient’s bloodstream after conditioning them to multiply more effectively. The cells are even more specific than targeted agents and directly activate the patient’s immune system against cancer, making the treatment more clinically effective. This is why they’re called ‘living drugs’.
How does it work?
In CAR T-cell therapy, the patient’s blood is drawn to harvest T-cells which are immune cells that play a major role in destroying tumour cells. Researchers modify these cells in the laboratory so that they express specific proteins on their surface, known as chimeric antigen receptors (CAR). They have an affinity for proteins on the surface of tumour cells. This modification in the cellular structure allows CAR T-cells to effectively bind to the tumour and destroy it.
The final step in the tumour’s destruction involves its clearance by the patient’s immune system.
Where is it used?
As of today, CAR T-cell therapy has been approved for leukaemias (cancers arising from the cells that produce white blood cells) and lymphomas (arising from the lymphatic system). These cancers occur through the unregulated reproduction of a single clone of cells, that is, following the cancerous transformation of a single type of cell, it produces millions of identical copies. As a result, the target for CAR T-cells is consistent and reliable.
CAR T-cell therapy is also used among patients with cancers that have returned after an initial successful treatment or which haven’t responded to previous combinations of chemotherapy or immunotherapy.
Its response rate is variable. In certain kinds of leukaemias and lymphomas, the efficacy is as high as 90%, whereas in other types of cancers it is significantly lower. The potential side-effects are also significant, associated with cytokine release syndrome (a widespread activation of the immune system and collateral damage to the body’s normal cells) and neurological symptoms (severe confusion, seizures, and speech impairment).
How widespread is its use?
The complexity of preparing CAR T-cells has been a major barrier to their use. The first clinical trial showing they were effective was published almost a decade ago; the first indigenously developed therapy in India was successfully performed only in 2022.
The technical and human resources required to administer this therapy are also considerable. Treatments in the U.S. cost more than a million dollars. Trials are underway in India, with companies looking to indigenously manufacture CAR T-cells at a fraction of the cost. The preliminary results have been encouraging.
Will this therapy be expensive in India as well?
In India, introducing any new therapy faces the twin challenges of cost and value. Critics argue that developing facilities in India may be redundant and/or inappropriate as even when it becomes cheaper, CAR T-cell therapy will be unaffordable to most Indians. Those who are affluent and require the therapy currently receive it abroad anyway.
While this is true, it may be the right answer to the wrong question. Having access to a global standard of care is every patient’s right; how it can be made more affordable can be the next step.
Investments in developing these technologies in India represent the hope that, as with other initially expensive treatments like robotic surgery, we will be able to provide economies of scale. The sheer volume of patients in India has the potential to drive the cost of treatment down.
What are ‘cell therapies’?
The interest in the technology goes beyond providing a new lease of life to people with leukaemias and lymphomas. Even for solid tumours — like those of the prostate, lung, colon, and some other organs — CAR T-cell therapy has shown results, particularly in patients whose tumours have recurred or have evaded multiple lines of treatment. The challenge with harnessing these techniques for solid tumours remains significant. These are highly heterogeneous cancers that lack a consistent target with which CAR T-cells can bind. Progress in the field, however, has the potential to unlock a host of newer treatments on the horizon called cell therapies. They include personalised anti-cancer vaccines and tumour infiltrating lymphocyte therapies (where white blood cells that attack the tumour are extracted, modified, and reintroduced into the patient).
Cancer constantly evolves to evade treatment; similarly, we also need to keep developing more sophisticated therapies with as few-side effects as possible. Cell therapies hold this promise and will also help us understand this dreaded disease and its complexities better.
2. India, Russia continue discussion to evolve a payment mechanism
New avenues: Denis Alipov speaking at a forum on India-Russia strategic partnership, in New Delhi on Monday.
The countries deliberate on payments in third currencies and sourcing from India as potential solutions to disruptions due to Western sanctions
With bilateral payments still not streamlined against the backdrop of Western sanctions, especially for defence deals, India and Russia are set to hold bilateral financial meetings under the framework of the Inter-Governmental Commission in the second half of February as part of ongoing efforts to iron out a mechanism, officials aware of the development said.
“We have agreed on a mechanism and we are fine-tuning it, continuous discussions are on. Enhancing bilateral trade and sourcing from India is one of the discussions, as also payments in third currencies,” an official source said.
Another major issue is transportation, with the challenge of finding cargo carriers — and their insurance — outside the purview of sanctions. Defence sources have expressed concerns regarding this since the beginning of the war in Ukraine. Insurance and reinsurance are under discussion, as well as efforts to avoid cargo ships under sanctions, the source said. On this, diplomatic sources stated that, increasingly, most of the shipping being used is Russian.
‘Banks too cautious’
Speaking at a seminar on Monday, Russian envoy in India Denis Alipov said that vostro accounts have been opened, the mechanism of rupee-rouble trade has been established, and it is now a matter for the banks to use it.
“Many Indian banks are overcautious. Using this mechanism would not invite any secondary restrictions from the U.S. if that is the fear. But still, banks want to be on the safe side,” Mr. Alipov said, adding that it would take some time for the knowledge that it is not detrimental for Indian banks to sink in, after which a positive expansion of this mechanism would be seen.
Budget documents presented last week show that the Indian Air Force has returned close to ₹2,370 crore from the Budget Estimates to the Revised Estimates for 2022-23. Official sources said that this was meant for payments to Russia as part of committed liabilities, which could not be completed. Payments for several other defence deals are held up as well, official sources said.
With Russia being shut out of the global SWIFT system for money transfers, India and Russia have agreed to conduct payments through the rupee-rouble arrangement. However, this has led to an accumulation of Indian rupees in Russian banks, given the large volume of payments. This is where both sides are discussing ways to enhance Russian sourcing from India.
3. ‘Oil still needed while world transitions to clean energy systems’
‘We can’t unplug current system before we have built the new one,’ says COP-28 president-designate, pushing for investment in decarbonisation
Despite the impressive growth of wind and solar power, renewable energy by itself will not be sufficient, particularly to transition industries that are entirely dependent on fossil fuel, according to Sultan Al Jaber, the president-designate of the next UN summit on climate change.
This year’s Conference of Parties (COP-28) of the UN Framework Convention on Climate Change will be hosted by the UAE, which holds one of the world’s largest oil and gas reserves.
Mr. Jaber is the UAE’s Minister for Industry and chief executive of the Abu Dhabi National Oil Company.
Carbon footprint
Speaking at the ongoing India Energy Week in Bengaluru on Tuesday, he pushed for more investment in minimising the carbon footprint of hydrocarbons.
“Without a breakthrough in battery storage, we must invest heavily in carbon capture, nuclear power, and the hydrogen value chain. But spending on these fundamental enablers of decarbonisation is less than 5% of what is spent on renewables. This must change. And when it comes to change, this also applies to the oil and gas industry. The world still needs hydrocarbons and will need them to bridge from the current energy system to the new one. We cannot unplug the current energy system before we have built the new one,” Mr. Al Jaber said.
He said that the world’s energy transition must be inclusive and deliver a fair deal to the Global South, a term for developing countries that includes both India and the UAE.
“We need to get more concessional finance to vulnerable communities around the world to lower risk, attract more private finance and turn billions into trillions,” Mr. Al Jaber said.
The COP-28 is slated to be held at Expo City Dubai between November 30 and December 12.
4. Editorial-1: Fiscal consolidation in the context of the Budget
Rangarajan is former Chairman, Prime Minister’s Economic Advisory Council and former Governor, Reserve Bank of India
A stronger fiscal consolidation road map is needed over the medium term
The Budget for 2023-24 has attempted to address the aspirations of different segments of society. It is a good effort in a difficult situation. But how far do the Budget provisions go to meet the two fundamental goals of growth and stability? The two must go together for sustained growth over the medium term, which will be the answer to many of India’s socioeconomic problems.
Budgetary support to growth
Growth is affected by the size of government expenditure and its revenue and capital components. Government expenditure is budgeted to grow at 7.5% while nominal GDP growth is estimated to fall from 15.4% in 2022-23 to 10.5% in 2023-24. Thus, the total expenditure relative to GDP is shown to fall from 15.3% in 2022-23 (RE) to 14.9% in 2023-24 (BE). The composition of government expenditure, however, would be growth positive.
Increase in the Centre’s capital expenditure is budgeted at 37% while that in revenue expenditure is only 1.2%. According to estimates by the Reserve Bank of India (2019, 2020), the multiplier associated with central government capital expenditure is 2.45, while that for revenue expenditure is 0.45. Investment expenditure by central public sector undertakings (PSUs) is budgeted to fall by 0.2% points.
However, State capital expenditures may increase as a result of central grants to the States meant for capital asset creation amounting to 1.2% of GDP, augmentation of States’ fiscal deficit to GDP ratio to 3.5%, and the facility of 50 years of interest-free loans for creating capital assets in 2023-24.
It is difficult to ascertain the extent to which States might utilise these facilities. Growth may also be stimulated indirectly due to an increase in private disposable incomes following tax slab adjustments applicable to the new income tax regime. Real growth in 2023-24 may be a little above 6%.
External conditions as reason
According to the Fiscal Responsibility and Budget Management (FRBM) Act, as amended in 2018, the Centre is mandated to take appropriate steps to limit its fiscal deficit to 3% of GDP by March 31, 2021 although this is an operational target. The mandated target pertains to the Centre’s debt-GDP ratio which is to be brought down to 40%. If there is a deviation from the fiscal deficit-GDP ratio of 3%, the Centre is required to state the reasons. In the medium-term fiscal policy cum Fiscal Policy Strategy Statement (MTFP), the Centre has attributed the deviation of the budgeted 5.9% fiscal deficit-GDP ratio to external economic conditions. For this reason, the Centre has also not provided the medium-term GDP growth forecasts.
Furthermore, the Centre has also not indicated the year by which it envisages reaching a fiscal deficit level of 3% of GDP. Instead, it has indicated that a level of 4.5% of GDP would be reached by 2025-26, calling for a steeper adjustment of 0.7% points each in the next two years. It might require another two to three years for reaching a level of 3%. However, even by this time, the mandated debt-GDP ratio of 40% would not be reached. The Centre’s debt-GDP level net of liabilities on account of investment in special securities of states under the National Social Security Fund (NSSF), is budgeted to increase from 55.7% in 2022-23 (RE) to 56.1% in 2023-24 (BE). This increase is expected as the primary deficit to GDP ratio is indicated at 2.3% in 2023-24.
The MTFP statement does not indicate the year by which the government aims to reach the mandated debt-GDP target of 40%. One implication of the high level of Centre’s debt-GDP ratio is for interest payments relative to revenue receipts, which is budgeted at 41% in 2023-24. This reduces, significantly, the space for primary expenditure in the Centre’s budget.
Private investment
For raising growth in the medium term, augmentation of private investment relative to GDP needs to be ensured. This requires that enough investible resources are left for the private sector after the public sector’s pre-emptive claim on these resources. At present, total investible resources, consisting of financial savings of the household sector amounting to about 8% of GDP and net foreign capital inflows amounting to 2.5% of GDP, may be estimated at 10.5% of GDP. The central and State fiscal deficits considered together may amount to 9.4% of GDP in 2023-24. This implies that only 1.1% is available for the private sector and the non-government public sector.
Investment of the Centre’s PSUs themselves amount to 1.1% of GDP in 2023-24, leaving little scope for State PSUs and the private sector. This is not amenable to creating an environment for interest rate reduction. In fact, trying to borrow beyond the available investible resources by the government can only lead to inflation. We know the dilemma faced by the government. Any further reduction in the fiscal deficit will cut expenditures which may not be appreciated. We need, however, a stronger fiscal consolidation road map over the medium term.
5. Opinion-1: Neglecting the health sector has consequences
India needs an infusion of resources and a bold imagination to address the problems of the sector.
The stagnant allocations in the Budget for health, education and nutrition reminded me of the film The Last Czars. Emperor Nicholas asks his communist captors why he has been imprisoned despite loving Russia and being loyal to it. The captor replies, “You loved Russia, but not the people.” In today’s world of governance, are Budgets a reasonable way of assessing this quality in our leaders for those who elected them?
Budgets are boring documents if we look at them only in terms of financial allocations to sectors. Yet, they are eagerly awaited because they validate the true intent and vision of the government — who or what it “loves” more. And such a judgment is based on the extent to which the Budget helps in furthering the equitable access of all citizens to basic public goods.
Soon after World War II left the U.K. devastated, the National Health Service was launched as a means to revive society.Envisioning a welfare state, the social economist William Beveridge sought to address the “five giant evils: want, disease, ignorance, squalor and idleness.” If India’s vision is driven by such an articulation, then investments need to be prioritised first towards basic services such as nutrition, health, employment, education, environmental sanitation and hygiene, rather than airports, highways and speed trains.
Fulfilling commitments
It may be argued that the government has been fair in this year’s Budget by providing free foodgrains to 80 crore poor people; developing 500 backward blocks; broadening access to housing, clean water, and toilets; providing employment through the rural employment guarantee scheme; and providing opportunities for skill development. But these can only have partial gains; they do not necessarily address the issue of widening inequality. Besides, for sustainable, long-term growth of the country, expanding universal access to high quality education, healthcare and nutrition (not just foodgrains but proteins and other supplementary foods that are currently unaffordable) is imperative. No country can go far if a significant proportion of its population is illiterate, unhealthy or malnourished. All the countries that are developed today invested well in education, health and nutrition. Studies in the U.S. show that after the Reagan era, innovation and scientific capability took a hit when public investment in education was reduced to push privatisation. Even Nicaragua, despite its economy being in shambles, invested in health and education. The tragedy is the failure of our political leadership, since Independence, in understanding the centrality of universal education and health to growth.
In view of the above, the Budget is disappointing. A study showed that 230 million Indians slid into poverty due to COVID-19. The ASER report shows the abysmal state of education — many Class 5 students are unable to read a Class 2 textbook. NFHS-5 data show that among children aged below five years, 35.5% were stunted and 32.1% were underweight. Yet, the allocations for education and nutrition are stagnant. The budget for midday meals reduced by 9%, not counting for inflation, even as data show a shift in enrolment from private to public schools with private schooling becoming unaffordable. Disease burden is rising with non-communicable diseases, mental health and geriatric care adding to the load of communicable diseases. India lacks adequate human resources, infrastructure and access to affordable diagnosis and treatment.
Fault lines
COVID-19 sharply brought into focus three major fault lines: the lack of financial risk protection, which is why citizens incurred huge expenses, estimated to be more than ₹70,000 crore, even as their incomes fell; a broken down primary health system, particularly in the north, that resulted in a large number of avoidable deaths; and the absence of well-equipped and functioning district hospitals to cope with demand. India needs an infusion of resources and a bold imagination to address these.
Besides, it also showed us the chaotic state of the regulatory framework. Many laws have serious infirmities and embed conflicts of interest. Some need to be scrapped and some amended, for without sound governance, opening up health to market forces can be disruptive and hurt patients, particularly the poor. COVID-19 also underscored the need to invest in public health to build our disease surveillance system and strengthen resilience to such shocks.
Addressing all this is urgent because there is no guarantee that the worst is over. It is the responsibility of a government to firewall its citizens against any such eventuality by improving the healthcare system and reducing vulnerability. We need political leadership backed by adequate funding in order to rebuild our public health system, promote scientific research, and expand health security. Constructing 157 nursing schools and trying the impossible of “eliminating” a genetic disease is no answer to these serious structural problems.
Equity and justice are values that must guide a polity to build a nation. Measuring policy and money allocation only in terms of political expediency is short-term and unsustainable. When such structures collapse, as they will, it is the poor and marginalised who will suffer disproportionately. But then disease is an equaliser — many rich people also died during COVID-19 for want of access to a hospital bed or oxygen. The price we paid then, and the lessons learned, need to be remembered. Neglecting the health sector and denying it of critical investments has consequences.
